Transcranial ultrasound stimulation modulates neural activities during NREM and REM depending on the stimulation phase of slow oscillations and theta waves in the hippocampus.

Modulation of the hippocampal neural activity by low-intensity transcranial ultrasound stimulation depends on the phase of theta rhythm and can also regulate sleep rhythm. However, until now, the modulatory effect of ultrasound stimulation on neural activity in different sleep states depending on the phase of local field potential stimulation in the hippocampus was unclear. To answer this question, closed-loop ultrasound stimulation was applied to in-phase (upstate)/out-of-phase slow oscillations in the hippocampus during non-rapid eye movement sleep, and to the peaks and troughs of theta oscillations in the hippocampus during wake in a mouse model. Local field potential of the hippocampus within 3-h after the ultrasound stimulation during light-on sleep cycle was recorded. We found that (i) under slow-oscillation in-phase stimulation, ultrasound stimulation upregulated the non-rapid eye movement ratio and decreased the wake ratio. Furthermore, it increased the ripple density during non-rapid eye movement and enhanced the coupling of the spindle-ripple during non-rapid eye movement as well as the theta-high gamma phase-amplitude coupling during the REM period. In addition, theta during the REM period showed a more stable oscillation mode. (ii) Under slow-oscillation out-of-phase stimulation, ultrasound stimulation increased the density of ripple during non-rapid eye movement and enhanced the theta-high gamma phase-amplitude coupling strength during REM. Furthermore, theta oscillations during REM were significantly slower and showed higher variability. (iii) Under the phase-locked peak and trough stimulation of theta oscillation, ultrasound stimulation increased the ripple density during non-rapid eye movement, weakened the coupling strength of spindle-ripple during non-rapid eye movement, and enhanced theta-high gamma phase-amplitude coupling during REM. However, theta oscillation mode was not changed significantly during REM. The above results suggest that the regulatory effect of ultrasound stimulation on neural activity in different sleep states depends on the stimulation phases of slow oscillations and theta waves in the hippocampus.

Transcranial ultrasound stimulation at the peak-phase of theta-cycles in the hippocampus improve memory performance.

The present study aimed to investigate the effectiveness of closed-loop transcranial ultrasound stimulation (closed-loop TUS) as a non-invasive, high temporal-spatial resolution method for modulating brain function to enhance memory. For this purpose, we applied closed-loop TUS to the CA1 region of the rat hippocampus for 7 consecutive days at different phases of theta cycles. Following the intervention, we evaluated memory performance through behavioral testing and recorded the neural activity. Our results indicated that closed-loop TUS applied at the peak phase of theta cycles significantly improves the memory performance in rats, as evidenced by behavioral testing. Furthermore, we observed that closed-loop TUS modifies the power and cross-frequency coupling strength of local field potentials (LFPs) during memory task, as well as modulates neuronal activity patterns and synaptic transmission, depending on phase of stimulation relative to theta rhythm. We demonstrated that closed-loop TUS can modulate neural activity and memory performance in a phase-dependent manner. Specifically, we observed that effectiveness of closed-loop TUS in regulating neural activity and memory is dependent on the timing of stimulation in relation to different theta phase. The findings implied that closed-loop TUS may have the capability to alter neural activity and memory performance in a phase-sensitive manner, and suggested that the efficacy of closed-loop TUS in modifying neural activity and memory was contingent on timing of stimulation with respect to the theta rhythm. Moreover, the improvement in memory performance after closed-loop TUS was found to be persistent.

[Modulation of motor responses and neural activities with transcranial ultrasound stimulation based on closed-loop control].

Closed-loop transcranial ultrasound stimulation technology is based on real-time feedback signals, and has the potential for precise regulation of neural activity. In this paper, firstly the local field potential (LFP) and electromyogram (EMG) signals of mice under different intensities of ultrasound stimulation were recorded, then the mathematical model of ultrasound intensity and mouse LFP peak/EMG mean was established offline based on the data, and the closed-loop control system of LFP peak and EMG mean based on PID neural network control algorithm was simulated and built to realize closed-loop control of LFP peak and EMG mean of mice. In addition, using the generalized minimum variance control algorithm, the closed-loop control of theta oscillation power was realized. There was no significant difference between the LFP peak, EMG mean and theta power under closed-loop ultrasound control and the given value, indicating a significant control effect on the LFP peak, EMG mean and theta power of mice. Transcranial ultrasound stimulation based on closed-loop control algorithms provides a direct tool for precise modulation of electrophysiological signals in mice.

Phase-locked closed-loop ultrasound stimulation modulates theta and gamma rhythms in the mouse hippocampus.

Previous studies have demonstrated that open-loop transcranial ultrasound stimulation (TUS) can modulate theta and gamma rhythms of the local field potentials (LFPs) in the mouse hippocampus; however, the manner in which closed-loop TUS with different pressures based on phase-locking of theta rhythms modulates theta and gamma rhythm remains unclear. In this study, we established a closed-loop TUS system, which can perform closed-loop TUS by predicting the peaks and troughs of the theta rhythm. Comparison of the power, sample entropy and complexity, and phase-amplitude coupling (PAC) between the theta and gamma rhythms under peak and trough stimulation of the theta rhythm revealed the following: (1) the variation in the absolute power of the gamma rhythm and the relative power of the theta rhythm under TUS at 0.6-0.8 MPa differ between peak and trough stimulation; (2) the relationship of the sample entropy of the theta and gamma rhythms with ultrasound pressure depends on peak and trough stimulation; and (3) peak and trough stimulation affect the PAC strength between the theta and gamma rhythm as a function of ultrasound pressure. These results demonstrate that the modulation of the theta and gamma rhythms by ultrasound pressure depends on peak and trough stimulation of the theta rhythm in the mouse hippocampus.

Modulation effect of mouse hippocampal neural oscillations by closed-loop transcranial ultrasound stimulation.

Objective. Closed-loop transcranial ultrasound stimulation (TUS) can be applied at a specific time according to the state of neural activity to achieve timely and precise neuromodulation and improve the modulation effect. In a previous study, we found that closed-loop TUS at the peaks and troughs of the theta rhythm in the mouse hippocampus was able to increase the absolute power and decrease the relative power of the theta rhythm of local field potentials (LFPs) independent of the peaks and troughs of the stimulus. However, it remained unclear whether the modulation effect of this closed-loop TUS-induced mouse hippocampal neural oscillation depended on the peaks and troughs of the theta rhythm.Approach. In this study, we used ultrasound with different stimulation modes and durations to stimulate the peaks (peak stimulation) and troughs (trough stimulation) of the hippocampal theta rhythm. The LFPs in the area of ultrasound stimulation were recorded and the amplitudes and power spectra of the theta rhythm before and after ultrasound stimulation were analyzed.Main results. The results showed that (a) the relative change in amplitude of theta rhythm decreases as the number of stimulation trials under peak stimulation increases; (b) the relative change in the absolute power of the theta rhythm decreases as the number of stimulation trials under peak stimulation increases; (c) the relative change in amplitude of the theta rhythm increases nonlinearly with the stimulation duration (SD) under peak stimulation, and; (d) the relative change in absolute power exhibits a nonlinear increase with SD under peak stimulation.Significance. These results suggest that the modulation effect of closed-loop TUS on theta rhythm is dependent on the stimulation mode and duration under peak stimulation. TUS has the potential to precisely modulate theta rhythm-related neural activity.