The Study On The Neuromodulation Effects Of Low Intensity Transcranial Ultrasound Stimulation On Temporal Lobe Epilepsy And AD

The study of treatment methods for central nervous system diseases is a key issue in the related fields such as medicine and neuroscience.Neuromodulation technologies have received widespread attention due to their therapeutic effects on various nervous system diseases.In recent years,low intensity transcranial ultrasound stimulation(LITUS)has become a new neuromodulation technology that has attracted much attention with the advantages of noninvasive,high spatial resolution,and high penetration depth.Temporal lobe epilepsy(TLE)and Alzheimer’s disease(AD)are two typical central nervous system diseases,in which TLE exhibits a large number of highly synchronized abnormal neuronal discharges,and AD electroencephalogram changes in complexity,synchronicity,and brain dynamics.LITUS has been found that has the potential to become a tool for treating TLE and AD,but the exact modulation effect and potential mechanism of LITUS on TLE and AD are still unclear.The closed loop neuromodulation technology plays a crucial role in neural information processing and the treatment of neurological diseases,while there are few reports on the research of closed loop transcranial ultrasound stimulation(CLTUS).Therefore,this article conducted studies on the neuromodulation effects of LITUS on TLE and AD,and established closed loop transcranial ultrasound stimulation system to achieve real-time modulation of hippocampal neural activity and temporal lobe epileptic seizure in mice.This paper mainly includes the following three parts:(1)The study for the neuromodulation effect of LITUS on seizures in mice with TLE.Taking the TLE mouse model induced by kainic acid as the research object,continuous LITUS and pulsed LITUS were applied to the hippocampus of the TLE mouse model,and the local field potentials(LFPs)of the hippocampus were recorded simultaneously.By analyzing the power spectrum,discharge frequency,epilepsy latency,phase amplitude coupling,complexity,approximate entropy,and maximum Lyapunov exponent characteristics of LFPs,the modulation mechanism of LITUS in suppressing temporal lobe epileptic seizure was studied in frequency domain,time domain,and nonlinear dynamics,demonstrating the neuromodulation effect of LITUS on TLE.(2)The study for the neuromodulation effect of LITUS in AD transgenic mice.With APP/PS1 AD transgenic mice as the research object,long term LITUS was applied to the hippocampus of AD mice for 15 minutes every day for 28 days,and the hippocampal LFPs and spike potentials were recorded.In addition,behavioral tests and biochemical analysis were conducted.LFPs applied power spectrum and phase amplitude coupling analysis,firing rates were applied after spike potentials classification,LFPs-spike potentials applied Theta-spike potentials phase locking analysis,and behavioral studies applied open field test,conditioned fear test and Morris water maze.What’s more,the β-amyloid and Tau protein levels in the hippocampus and cortex of AD mice were detected.The modulation mechanism of LITUS on AD mice was studied from behavior,biochemical indicators,and neural oscillation,demonstrating the neuromodulation effect of LITUS on AD.(3)The study on real-time noninvasive neuromodulation of CLTUS system in vivo.In the study of neural activity,LFPs in the hippocampus of normal mice were recorded and the peak and trough times based on the period of Theta rhythm were predicted to perform CLTUS.The power changes before and after stimulation were analyzed to study the modulation effect of CLTUS on neural activity.The seizure of temporal lobe epilepsy is more intuitive in electroencephalogram than AD,LFPs in the hippocampus of TLE model mice were recorded and the seizure of temporal lobe epilepsy was detected based on amplitude standard deviation and coastline coefficient features to perform CLTUS.The modulation effect of CLTUS on temporal lobe epilepsy was studied by analyzing the differences in epilepsy latency and duration of seizure under CLTUS and sham stimulation.A closed loop low intensity transcranial ultrasound stimulation system was established to achieve real-time modulation of hippocampal neural activity and temporal lobe epileptic seizure in mice,demonstrating that CLTUS can not only modulate neural activity through specific phase stimulation of the Theta rhythm in the hippocampus,but also timely and effectively suppress seizures in TLE mice.