Investigation of Neuromodulation Effect of Cerebellum-targeted Low Intensity Transcranial Pulsed Ultrasound Stimulation

The cerebellum, despite its small volume, houses approximately 80% of the neurons in the central nervous system. Traditionally, it has been regarded as a region related to motor function, but recent studies suggest its functionality extends well beyond that. The cerebellum maintains extensive connections with numerous brain regions, either directly or indirectly. For instance, it has been shown that electrical and optogenetic stimulation can modulate hippocampal neural activities and alter object-location processing mediated by the hippocampus. Furthermore, electrical stimulation at cerebellum can potentially suppress seizures of temporal lobe epilepsy primarily originating from the hippocampus. This suggests that the cerebellum is an attractive target for neuromodulation, both for neuroscience study and clinical application. However, the invasive nature of electrical stimulation and the need for genetic modification in optogenetic stimulation make them less desirable for translational application. In contrast, low-intensity transcranial focused ultrasound stimulation (tFUS) has recently emerged as a promising neuromodulation technique due to its non-invasive nature, ability to penetrate deeply, and high spatial resolution. Does cerebellum-targeted tFUS also generate a diverse range of neural responses, akin to other neuromodulation methods? Can it also result in beneficial clinical applications, such as seizure suppression in epilepsy? To our knowledge, these questions have not yet been systematically addressed. New findings in these areas could shed light on how tFUS impacts our neural system and could also enhance the immediate translational value of tFUS.  In our proposed study, we aim to delve into how tFUS targeting the cerebellum can modulate neural activities in the hippocampus and other broad brain regions, using a wide array of stimulus parameters. Our preliminary results suggest the potential to alter the strength or even direction of the neural spike response in non-target sites. We plan to further characterize the effect of different stimulus parameters and identify parameter sets that can provide more predictable excitatory or inhibitory responses in the non-target areas. We will then apply these findings to a rat model of epilepsy to test the effectiveness of cerebellum-targeted tFUS on seizure suppression. We believe our proposed study could unveil the cerebellum's potential as a new target for non-invasive neuromodulation intervention.