Transcranial ultrasound neuromodulation facilitates isoflurane-induced general anesthesia recovery and improves cognition in mice.

Delayed arousal and cognitive dysfunction are common, especially in older patients after general anesthesia (GA). Elevating central nervous system serotonin (5-HT) levels can promote recovery from GA and increase synaptic plasticity to improve cognition. Ultrasound neuromodulation has become a noninvasive physical intervention therapy with high spatial resolution and penetration depth, which can modulate neuronal excitability to treat psychiatric and neurodegenerative diseases. This study aims to use ultrasound to noninvasively modulate the brain 5-HT levels of mice to promote recovery from GA and improve cognition in mice. The dorsal raphe nucleus (DRN) of mice during GA was stimulated by the 1.1 MHz ultrasound with a negative pressure of 356 kPa, and the liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) method was used to measure the DRN 5-HT concentrations. The mice's recovery time from GA was assessed, and the cognition was evaluated through spontaneous alternation Y-maze and novel object recognition (NOR) tests. After ultrasound stimulation, the mice's DRN 5-HT levels were significantly increased (control: 554.0 ± 103.2 ng/g, anesthesia + US: 664.2 ± 84.1 ng/g, *p = 0.0389); the GA recovery time (return of the righting reflex (RORR) emergence latency time) of mice was significantly reduced (anesthesia: 331.6 ± 70 s, anesthesia + US: 223.2 ± 67.7 s, *p = 0.0215); the spontaneous rotation behavior score of mice was significantly increased (anesthesia: 59.46 ± 5.26 %, anesthesia + US: 68.55 ± 5.24 %; *p = 0.0126); the recognition index was significantly increased (anesthesia: 55.02 ± 6.23 %, anesthesia + US: 78.52 ± 12.21 %; ***p = 0.0009). This study indicates that ultrasound stimulation of DRN increases serotonin levels, accelerates recovery from anesthesia, and improves cognition, which could be an important strategy for treating delayed arousal, postoperative delirium, or even lasting cognitive dysfunction after GA.

Ultrasound neuromodulation ameliorates chronic corticosterone-induced depression- and anxiety-like behaviors in mice.

Objective.Monoamine dysfunction has been implicated as a pathophysiological basis of several mental disorders, including anxiety and depression. Transcranial ultrasound stimulation (TUS) is a noninvasive nerve stimulation technic showing great potential in treating depression/anxiety disorders. This study aims to investigate whether TUS can ameliorate depression with anxiety in mice by regulating brain monoamine levels.Approach.Mice received repeated subcutaneous injections of corticosterone (CORT, 20 mg kg-1) for 3 weeks to produce depression- and anxiety-like behaviors. Ultrasound stimulated the dorsal lateral nucleus (DRN) for 30 min daily for 3 weeks without interruption of CORT injection. Behavioral phenotypes of depression and anxiety were estimated by sucrose preference test (SPT), tail suspension test (TST), and elevated plus-maze test (EPM). Liquid chromatography-mass spectrometry (LC-MS) was used to quantify brain levels of serotonin (5-HT), norepinephrine (NE), and dopamine (DA). Western blotting was performed to detect brain-derived neurotrophic factor (BDNF) levels in hippocampal.Main results.TUS of DRN significantly ameliorated the depression-like behaviors in SPT (p= 0.0004) and TST (p= 0.0003) as well as anxiety-like behaviors in EPM (open arm entry frequencies,p< 0.05). Moreover, TUS increased c-Fos-positive cell expression (p= 0.0127) and induced no tissue damage. LC-MS results showed TUS of DRN resulted in a non-significant increase in the 5-HT levels and a significant decrease in the NE levels, but did not affect the levels of DA and BDNF.Significance.These results suggest TUS of DRN has safely and effectively ameliorated CORT-induced depression- and anxiety-like behaviors, possibly by restoring brain levels of 5-HT and NE. TUS may be a safe and effective technique for remedying depression and anxiety comorbidity.

Simultaneous multi-target ultrasound neuromodulation in freely-moving mice based on a single-element ultrasound transducer.

Objective.Ultrasound neuromodulation has become an emerging method for the therapy of neurodegenerative and psychiatric diseases. The phased array ultrasonic transducer enables multi-target ultrasound neuromodulation in small animals, but the relatively large size and mass and the thick cables of the array limit the free movement of small animals. Furthermore, spatial interference may occur during multi-target ultrasound brain stimulation with multiple micro transducers.Approach.In this study, we developed a miniature power ultrasound transducer and used the virtual source time inversion method and 3D printing technology to design, optimize, and manufacture the acoustic holographic lens to construct a multi-target ultrasound neuromodulation system for free-moving mice. The feasibility of the system was verified byin vitrotranscranial ultrasound field measurements,in vivodual-target blood-brain barrier (BBB) opening experiments, andin vivodual-target ultrasound neuromodulation experiments.Main results.The developed miniature transducer had a diameter of 4.0 mm, a center frequency of 1.1 MHz, and a weight of 1.25 g. The developed miniature acoustic holographic lens had a weight of 0.019 g to generate dual-focus transcranial ultrasound. The ultrasonic field measurements' results showed that the bifocal's horizontal distance was 3.0 mm, the -6 dB focal spot width in thex-direction was 2.5 and 2.25 mm, and 2.12 and 2.24 mm in they-direction. Finally, thein vivoexperimental results showed that the system could achieve dual-target BBB opening and ultrasound neuromodulation in freely-moving mice.Significance.The ultrasonic neuromodulation system based on a miniature single-element transducer and the miniature acoustic holographic lens could achieve dual-target neuromodulation in awake small animals, which is expected to be applied to the research of non-invasive dual-target ultrasonic treatment of brain diseases in awake small animals.

Transcranial ultrasound stimulation relieves depression in mice with chronic restraint stress.

Objective.Exhaustion of Serotonin (5-hydroxytryptamine, 5-HT) is a typical cause of the depression disorder's development and progression, including depression-like behaviors. Transcranial ultrasound stimulation (TUS) is an emerging non-invasive neuromodulation technique treating various neurodegenerative diseases. This study aims to investigate whether TUS ameliorates depression-like behaviors by restoring 5-HT levels.Methods.The depression model mice are established by chronic restraint stress (CRS). Ultrasound waves (FF = 1.1 MHz, PRF = 1000 Hz, TBD = 0.5 ms, SD = 1 s, ISI = 1 s, and DC = 50%) were delivered into the dorsal raphe nucleus (DRN) for 30 min per day for 2 weeks. Depression-like behavior changes are evaluated with the sucrose preference and tail suspension tests. Liquid chromatography-mass spectrometry is performed to quantitatively detect the concentration of 5-HT in the DRN to explore its potential mechanism. The effectiveness and safety of TUS were assessed by c-Fos immunofluorescence and hematoxylin and eosin (HE) staining, respectively.Results.Three weeks after CRS, 22 depressive mice models were screened by sucrose preference index (SPI). After 2 weeks of ultrasound stimulation of the DRN (DRN-TUS) in depressive mice, the SPI was increased (p= 0.1527) and the tail suspension immobility duration was significantly decreased (p= 0.0038) compared with the non-stimulated group. In addition, TUS significantly enhances the c-Fos (p= 0.05) positive cells' expression and the 5-HT level (p= 0.0079) in the DRN. Importantly, HE staining shows no brain tissue damage.Conclusion.These results indicate that DRN-TUS has safely and effectively improved depression-like behaviors including anhedonia and hopelessness, potentially by reversing the depletion of 5-TH.SignificanceTUS may provide a new perspective on depression therapy, possibly through restoring monoamine levels.

Multitarget Transcranial Ultrasound Therapy in Small Animals Based on Phase-Only Acoustic Holographic Lens.

Transcranial ultrasound therapy has become a noninvasive method for treating neurological and psychiatric disorders, and studies have further demonstrated that multitarget transcranial ultrasound therapy is a better solution. At present, multitarget transcranial ultrasound therapy in small animals can only be achieved by the multitransducer or phased array. However, multiple transducers may cause spatial interference, and the phased array system is complicated, expensive, and especially unsuitable for small animals. This study is the first to design and fabricate a miniature acoustic holography lens for multitarget transcranial ultrasound therapy in rats. The acoustic holographic lens, working at a frequency of 1.0 MHz, with a size of 10.08 mm ×10.08 mm and a pixel resolution of 0.72 mm, was designed, optimized, and fabricated. The dual-focus transcranial ultrasound generated based on the lens was measured; the full-width at half-maximum (FWHM) of the focal spots in the y -direction was 2.15 and 2.27 mm and in the z -direction was 2.3 and 2.36 mm. The focal length was 5.4 mm, and the distance between the two focuses was 5.6 mm, close to the desired values of 5.4 and 6.0 mm. Finally, the multiple-target blood-brain barrier opening in rats' bilateral secondary visual cortex (mediolateral area, V2ML) was demonstrated using the transcranial ultrasound therapy system based on the lens. These results demonstrate the good performance of the multitarget transcranial ultrasound therapy system for small animals, including high spatial resolution, small size, and low cost.

Value of serum miR-922 and miR-506 expression levels in the diagnosis and prognostic assessment of childhood acute lymphoblastic leukemia. / è¡€æ¸ miR-922及miR-506å¯¹å„¿ç«¥æ€¥æ€§æ·‹å·´ç»†èƒžç™½è¡€ç— è¯Šæ–­åŠé¢„åŽåˆ¤æ–­çš„ä»·å€¼.

OBJECTIVES: To study the value of serum miR-922 and miR-506 expression levels in the diagnosis and prognostic assessment of childhood acute lymphoblastic leukemia (ALL). METHODS: A total of 132 children with ALL (ALL group) and 80 healthy children (healthy control group) were prospectively selected in this study. Quantitative real-time polymerase chain reaction was used to measure the expression levels of serum miR-922 and miR-506 in both groups. Receiver operating characteristic (ROC) curves were plotted to analyze the diagnostic value of miR-922 and miR-506 for childhood ALL. The Kaplan-Meier method was used to plot survival curves, and multivariate COX regression models were used to analyze the risk factors for poor prognosis in children with ALL. RESULTS: The ALL group had significantly higher expression levels of serum miR-922 and miR-506 than the control group (P<0.001). The ROC curve analysis showed that the optimal cut-off values of miR-922 and miR-506 for the diagnosis of childhood ALL were 1.46 and 2.17, respectively. The high miR-922 expression (≥1.46) group and high miR-506 expression (≥2.17) group had significantly higher incidence rates of lymph node enlargement, leukocyte count ≥50×109/L, medium-high risk stratification, mixed-lineage leukemia (MLL) gene rearrangement, and karyotype abnormality than the low miR-922 expression group and low miR-506 expression group (P<0.05). The Kaplan-Meier analysis showed that high expression of miR-922 and miR-506 was associated with short survival time in children with ALL (P<0.05). The multivariate COX regression analysis showed that leukocyte count ≥50×109/L, medium-high risk stratification, MLL gene rearrangement, miR-922≥1.46, and miR-506≥2.17 could indicate poor prognosis in children with ALL (P<0.05). CONCLUSIONS: The expression levels of miR-922 and miR-506 are of good value in the diagnosis and prognostic assessment of childhood ALL.

Perovskite-Enhanced Silicon-Nanocrystal Optoelectronic Synaptic Devices for the Simulation of Biased and Correlated Random-Walk Learning.

Silicon- (Si-) based optoelectronic synaptic devices mimicking biological synaptic functionalities may be critical to the development of large-scale integrated optoelectronic artificial neural networks. As a type of important Si materials, Si nanocrystals (NCs) have been successfully employed to fabricate optoelectronic synaptic devices. In this work, organometal halide perovskite with excellent optical asborption is employed to improve the performance of optically stimulated Si-NC-based optoelectronic synaptic devices. The improvement is evidenced by the increased optical sensitivity and decreased electrical energy consumption of the devices. It is found that the current simulation of biological synaptic plasticity is essentially enabled by photogating, which is based on the heterojuction between Si NCs and organometal halide perovskite. By using the synaptic plasticity, we have simulated the well-known biased and correlated random-walk (BCRW) learning.

Optically Stimulated Synaptic Devices Based on the Hybrid Structure of Silicon Nanomembrane and Perovskite.

Optoelectronic synaptic devices have been attracting increasing attention due to their critical role in the development of neuromorphic computing based on optoelectronic integration. Here we start with silicon nanomembrane (Si NM) to fabricate optoelectronic synaptic devices. Organolead halide perovskite (MAPbI3) is exploited to form a hybrid structure with Si NM. We demonstrate that synaptic transistors based on the hybrid structure are very sensitive to optical stimulation with low energy consumption. Synaptic functionalities such as excitatory post-synaptic current (EPSC), paired-pulse facilitation, and transition from short-term memory to long-term memory (LTM) are all successfully mimicked by using these optically stimulated synaptic transistors. The backgate-enabled tunability of the EPSC of these devices further leads to the LTM-based mimicking of visual learning and memory processes under different mood states. This work contributes to the development of Si-based optoelectronic synaptic devices for neuromorphic computing.