Transcranial magneto-acoustical stimulation (TMAS) uses ultrasonic waves and a static magnetic field to generate electric current in nerve tissues for the purpose of modulating neuronal activities. It has the advantage of high spatial resolution and penetration depth. Neuronal firing rhythms carry and transmit nerve information in neural systems. In this study, we investigated the phase-locking characteristics of neuronal firing rhythms with TMAS based on the Hodgkin-Huxley neuron model. The simulation results indicate that the modulation frequency of ultrasound can affect the phase-locking behaviors. The results of this study may help us to explain the potential firing mechanism of TMAS.

The closed-loop brain stimulation technique plays a key role in neural network information processing and therapies of neurological diseases. Transcranial ultrasound stimulation (TUS) is an established neuromodulation method for the neural oscillation in animals or human. All available TUS systems provide brain stimulation in an open-loop pattern. In this study, we developed a closed-loop transcranial ultrasound stimulation (CLTUS) system for real-time non-invasive neuromodulation in vivo. We used the CLTUS system to modulate the neural activities of the hippocampus of a wild-type mouse based on the phase of the theta rhythm recorded at the ultrasound-targeted location. In addition, we modulated the hippocampus of a temporal lobe epilepsy (TLE) mouse. The ultrasound stimulation increased the absolute power and reduced the relative power of the theta rhythm, which were independent of the specific phase of the theta rhythm. Compared with those of a sham stimulation, the latency of epileptic seizures was significantly increased, while the epileptic seizure duration was significantly decreased under the CLTUS. The above results indicate that the CLTUS can be used to not only modulate the neural oscillation through the theta-phase-specific manipulation of the hippocampus but also effectively inhibit the seizure of a TLE mouse in time. CLTUS has large application potentials for the understanding of the causal relationship of neural circuits as well as for timely, effective, and non-invasive therapies of neurological diseases such as epilepsy and Parkinson's disease.

Low-intensity pulsed ultrasound stimulation (LIPUS) can inhibit seizures associated with temporal lobe epilepsy (TLE), which is the most common epileptic syndrome in adults and accounts for more than half of the cases of intractable epilepsy. Electroencephalography (EEG) signal analysis is an important method for studying epilepsy. The nonlinear dynamics of epileptic EEG signals can be used as biomarkers for the prediction and diagnosis of epilepsy. However, how ultrasound modulates the nonlinear dynamic characteristics of EEG signals in TLE is still unclear. Here, we used low-intensity pulsed ultrasound to stimulate the CA3 region of kainite (KA)-induced TLE mice, simultaneously recorded local field potentials (LFP) in the stimulation regions before, during, and after LIPUS. The nonlinear characteristics, including complexity, approximate entropy of different frequency bands, and Lyapunov exponent of the LFP, were calculated. Compared with the control group, the experimental group showed that LIPUS inhibited TLE seizure and the complexity, approximate entropy of the delta (0.5–4 Hz) and theta (4–8 Hz) frequency bands, and Lyapunov exponent of the LFP significantly increased in response to ultrasound stimulation. The values before ultrasound stimulation were higher ∼1.87 (complexity), ∼1.39 (approximate entropy of delta frequency bands), ∼1.13 (approximate entropy of theta frequency bands) and ∼1.46 times (Lyapunov exponent) than that after ultrasound stimulation ( p < 0.05). The above results demonstrated that LIPUS can alter nonlinear dynamic characteristics and provide a basis for the application of ultrasound stimulation in the treatment of epilepsy.

Although there is increasing use of focused ultrasound stimulation (FUS) in brain studies, the real-time changes of the cerebral blood flow (CBF) due to FUS remain unclear. In this study, we developed a novel scheme combining FUS and laser speckle contrast imaging, which can be used to measure the CBF caused by FUS in real time. The results showed that the change of CBF increased from 0 to 30 s and reached up to the maximum of 115.1 ± 6.5% at 30 s and then decreased gradually from 30 to 60 s. This study demonstrates that FUS was able to increase CBF and alter cortical hemodynamic responses, which indicates that FUS is a potential non-invasive method to study ischemic stroke rehabilitation.

Several studies have separately investigated neural activities and hemodynamic responses induced by low-intensity pulsed ultrasound stimulation (LIPUS), less is known about their coupling under LIPUS. This study aims to investigate the neurovascular coupling with LIPUS by measuring neural activity and hemodynamics. We found that the relative power and sample entropy of local field potential at the ripple band have a significant correlation to relative cerebral blood flow over time (correlation coefficients: 0.66 ± 0.13 [P < 0.01] and -0.58 ± 0.11 [P < 0.05]). These results demonstrate that LIPUS can induce neurovascular coupling in the mouse visual cortex.

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The immune checkpoint blockade (ICB) faces a low response rate in clinical cancer treatment. Chemotherapy could enhance the response rate of the ICB, but patients would suffer from side effects. The off-target toxicity could be reduced by loading the chemotherapeutic agent through nanocarriers. Therefore, we developed a polymeric carrier for doxorubicin (DOX) loading to form DOX nanoparticles (DOX NPs), which were spatiotemporally responsive to the tumor microenvironment (TME). DOX NPs had an efficient transcytosis property for deep tumor infiltration and sustained drug release ability. Unfortunately, a binary therapy of DOX NPs and ICB induces tumor adaptive resistance and causes dynamic deterioration of the TME. We propose for the first time that TGF-β1 is a major cause of tumor adaptive resistance and developed an immune cocktail therapy containing DOX NPs, ICB, and TGF-β1 gene silencing nanoparticles. This therapy successfully overcame tumor adaptive resistance by reversing the immunosuppressive TME and achieved enhanced tumor treatment efficiency.

BackgroundPulsed transcranial ultrasound stimulation (pTUS) can modulate the neuronal activity of motor cortex and elicit muscle contractions. Cortico-muscular coupling (CMC) can serve as a tool to identify interaction between the oscillatory activity of the motor cortex and effector muscle. This research aims to explore the neuromodulatory effect of low-intensity, pTUS with different number of tone burst to neural circuit of motor-control system by analyzing the coupling relationship between motor cortex and tail muscle in mouse. The motor cortex of mice was stimulated by pulsed transcranial ultrasound with different number of tone bursts (NTB = 100 150 200 250 300). The local field potentials (LFPs) in tail motor cortex and electromyography (EMG) in tail muscles were recorded simultaneously during pTUS. The change of integral coupling strength between cortex and muscle was evaluated by mutual information (MI). The directional information interaction between them were analyzed by transfer entropy (TE).ResultsAlmost all of the MI and TE values were significantly increased by pTUS. The results of MI showed that the CMC was significantly enhanced with the increase of NTB. The TE results showed the coupling strength of CMC in descending direction (from LFPs to EMG) was significantly higher than that in ascending direction (from EMG to LFPs) after stimulation. Furthermore, compared to NTB = 100, the CMC in ascending direction were significantly enhanced when NTB = 250, 300, and CMC in descending direction were significantly enhanced when NTB = 200, 250, 300.ConclusionThese results confirm that the CMC between motor cortex and the tail muscles in mouse could be altered by pTUS. And by increasing the NTB (i.e. sonication duration), the coupling strength within the cortico-muscular circuit could be increased, which might further influence the motor function of mice. It demonstrates that, using MI and TE method, the CMC could be used for quantitatively evaluating the effect of pTUS with different NTBs, which might provide a new insight into the effect of pTUS neuromodulation in motor cortex.