The Effects Of Low-intensity Transcranial Ultrasound Stimulation On Neuromodulation In Parkinson’s Disease Mice

Parkinson’s disease(PD)is a neurodegenerative disorder that significantly reduces patients’ motor and cognitive abilities,profoundly impacting their quality of life and imposing substantial burdens on patients,their families,and society.Low-intensity transcranial ultrasound stimulation(TUS),as a safe,non-invasive,deeply penetrating,and highly spatially resolving neuro-modulation technology,holds promise for PD treatment.However,due to limited understanding of the effects and mechanisms of TUS therapy for PD,its practical application remains elusive.To address these issues,this paper investigates the application of TUS in the treatment of PD model mice.Focusing on the motor and cognitive impairments induced by the disease,this research systematically studies the effects of TUS stimulation on the behavior,neural oscillations,and neuronal structure and function in PD model mice using behavioral tests,local field potential and spike recordings,dendritic spine and calcium imaging methods.Additionally,it explores the neuro-modulatory effects of different patterns and intensities of TUS on the cerebellar-cortical loop.This study innovatively applies TUS in treating motor and memory impairments in PD model mice and elucidates potential neural mechanisms underlying TUS therapy for PD.The paper comprises the following sections:(1)Behavioral tests involving free movement experiments,swimming experiments,and hanging experiments were conducted on PD model mice.The analysis involved tracking the mice’s movement trajectories and assessing activity time,distance traveled,swimming distance,and similar metrics.Results demonstrate that continuous TUS stimulation for 4 days improves the motor function of PD model mice,with the therapeutic effect gradually enhancing with prolonged TUS duration.(2)Behavioral tests on novel object recognition in PD model mice were conducted while recording local field potentials and spikes in the hippocampal CA1 region.Through analyzing the exploration time of new objects and neural oscillation features,it was evidenced that continuous TUS stimulation for 4 days enhances the working memory of PD model mice.It significantly increases the relative power of theta,low gamma,and high gamma frequency bands in local field potentials and strengthens the phase-amplitude coupling between theta-low gamma and theta-high gamma.It also biases the firing of intermediate neurons towards the rising phase of theta frequency in local field potentials(180°-360°).This demonstrates that TUS might improve the working memory of PD model mice by closely modulating neural activity in the CA1 brain region using ultrasound.(3)Behavioral tests involving whisker-dependent novel object recognition in PD model mice were conducted,and dendritic spine and calcium fluorescence images in the barrel cortex were collected.Analysis of the time spent by the mice exploring new objects using their whiskers,the number of dendritic spines,and calcium activity characteristics demonstrated that 4 days of continuous TUS stimulation enhances the whisker-dependent novel object recognition ability of mice.It significantly increases neuronal firing activity,enhances dendritic spine growth rates,without affecting spine elimination rates,thereby promoting synaptic plasticity.This indicates that TUS can enhance mice’s learning and memory abilities along with closely associated neuronal firing activity and synaptic plasticity.(4)TUS stimulation was applied to the mouse cerebellum,and real-time calcium activity images of the contralateral primary motor cortex were collected during stimulation.By varying ultrasound duty cycles and intensities,different patterns and intensities of TUS-induced activity patterns in cerebellar-induced primary motor cortex pyramidal neurons were summarized.This provides a theoretical foundation for the application of TUS in modulating the cerebellar-motor cortex loop.