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Modulating basal ganglia circuitry is of great significance in the improvement of motor function in Parkinson’s disease (PD). Here, for the first time, we demonstrate that noninvasive ultrasound deep brain stimulation (UDBS) of the subthalamic nucleus (STN) or the globus pallidus (GP) improves motor behavior in a subacute mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Immunohistochemical c-Fos protein expression confirms that there is a relatively high level of c-Fos expression in the STN-UDBS and GP-UDBS group compared with sham group (both p < 0.05). Furthermore, STN-UDBS or GP-UDBS significantly increases the latency to fall in the rotarod test on day 9 (p < 0.05) and decreases the time spent climbing down a vertical rod in the pole test on day 12 (p < 0.05). Moreover, our results reveal that STN-UDBS or GP-UDBS protects the dopamine (DA) neurons from MPTP neurotoxicity by downregulating Bax (p < 0.001), upregulating Bcl-2 (p < 0.01), blocking cytochrome c (Cyt C) release from mitochondria (p < 0.05), and reducing cleaved-caspase 3 activity (p < 0.01) in the ipsilateral substantia nigra (SN). Additionally, the safety of ultrasound stimulation is characterized by hematoxylin and eosin (HE) and Nissl staining; no hemorrhage or tissue damage is detected. These data demonstrate that UDBS enables modulation of STN or GP neural activity and leads to neuroprotection in PD mice, potentially serving as a noninvasive strategy for the clinical treatment of PD.

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Ultrasound stimulation, as a novel and noninvasive technique for neuromodulation, shows a great potential in the treatment of functional brain diseases. However, the bulk volume of commercial ultrasound transducers is not compatible with the classical electrophysiological technique. Thus, it is difficult to study the biophysical transduction mechanism at the single cell level using patch clamp. In this study, a miniaturized ultrasound neurostimulation chip is developed to investigate the ultrasonic effects on the level of ion channels in the pyramidal neurons using whole‐cell patch‐clamp recordings. Any kind of streaming of molecules in water is disregarded. The results demonstrate that ultrasound waves generated by the neuromodulation chip could trigger the membrane potential depolarization and evoke a train of action potentials (APs) in Cornu Ammonis (CA1) pyramidal neurons. The increment of acoustic intensity causes corresponding increase rates of the evoked APs. Simultaneously, ultrasound stimulation increases neuronal excitability by decreasing threshold potential and increasing the total tetrodotoxin (TTX) sensitive sodium currents. Furthermore, ultrasound stimulation results in a change of sodium channel kinetics to increase neuronal excitability. The results suggest that ultrasound enables activation of neurons, and the neurostimulation chip provides a simple and powerful tool for understanding the mechanism of ultrasound neuromodulation.

Ultrasound stimulation has recently emerged as a non-invasive method for modulating brain activity in animal and human studies with healthy subjects. Whether brain diseases such as Alzheimer's disease, epilepsy, and depression can be treated using ultrasound stimulation still needs to be explored. Recent studies have reported that ultrasound stimulation suppressed epileptic seizures in a rodent model of epilepsy. These findings raise the crucial question of whether ultrasound stimulation can inhibit seizures in non-human primates with epilepsy. Here, we addressed this critical question. We confirmed that ultrasound stimulation significantly reduced the frequency of seizures in acute epileptic monkeys. Furthermore, the results showed that the number and duration of seizures were reduced, whereas the inter-seizure interval was increased after ultrasound stimulation. Besides, no significant brain tissue damage was observed by T2-weighted MR imaging. Our results are of great importance for future clinical applications of ultrasound neuromodulation in patients with epilepsy.

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Potassium channels (K + ) play an important role in the regulation of cellular signaling. Dysfunction of potassium channels is associated with several severe ion channels diseases, such as long QT syndrome, episodic ataxia and epilepsy. Ultrasound stimulation has proven to be an effective non-invasive tool for the modulation of ion channels and neural activity. In this study, we demonstrate that ultrasound stimulation enables to modulate the potassium currents and has an impact on the shape modulation of action potentials (AP) in the hippocampal pyramidal neurons using whole-cell patch-clamp recordings in vitro . The results show that outward potassium currents in neurons increase significantly, approximately 13%, in response to 30 s ultrasound stimulation. Simultaneously, the increasing outward potassium currents directly decrease the resting membrane potential (RMP) from −64.67 ± 1.10 mV to −67.51 ± 1.35 mV. Moreover, the threshold current and AP fall rate increase while the reduction of AP half-width and after-hyperpolarization peak time is detected. During ultrasound stimulation, reduction of the membrane input resistance of pyramidal neurons can be found and shorter membrane time constant is achieved. Additionally, we verify that the regulation of potassium currents and shape of action potential is mainly due to the mechanical effects induced by ultrasound. Therefore, ultrasound stimulation may offer an alternative tool to treat some ion channels diseases related to potassium channels.