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Background:. Deep brain stimulation (DBS) has seizure-suppressing effects but the molecular mechanisms underlying its therapeutic action remain unclear. This study aimed to systematically elucidate the mechanisms underlying DBS-induced seizure suppression at a molecular level. Methods:. We established a macaque model of mesial temporal lobe epilepsy (mTLE), and continuous high-frequency hippocampus DBS (hip-DBS) was applied for 3 months. The effects of hip-DBS on hippocampus gene expression were examined using high-throughput microarray analysis followed by bioinformatics analysis. Moreover, the microarray results were validated using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analyses. Results:. The results showed that chronic hip-DBS modulated the hippocampal gene expression. We identified 4119 differentially expressed genes and assigned these genes to 16 model profiles. Series test of cluster analysis showed that profiles 5, 3, and 2 were the predominant expression profiles. Moreover, profile 5 was mainly involved in focal adhesion and extracellular matrix-receptor interaction pathway. Nine dysregulated genes (Arhgap5, Col1a2, Itgb1, Pik3r1, Lama4, Fn1, Col3a1, Itga9, and Shc4) and three genes (Col1a2, Itgb1, and Flna) in these two pathways were further validated by qRT-PCR and Western blot analyses, respectively, which showed a concordance. Conclusion:. Our findings suggest that hip-DBS could markedly reverse mTLE-induced abnormal gene expression. Findings from this study establish the basis for further investigation of the underlying regulatory mechanisms of DBS for mTLE.

We report infrared (IR) pulse laser-activated highly efficient parallel intracellular delivery by using an array of titanium microdish (TMD) device. Upon IR laser pulse irradiation, a two-dimensional array of TMD device generated photothermal cavitation bubbles to disrupt the cell membrane surface and create transient membrane pores to deliver biomolecules into cells by a simple diffusion process. We successfully delivered the dyes and different sizes of dextran in different cell types with variations of laser pulses. Our platform has the ability to transfect more than a million cells in a parallel fashion within a minute. The best results were achieved for SiHa cells with a delivery efficiency of 96% and a cell viability of around 98% for propidium iodide dye using 600 pulses, whereas a delivery efficiency of 98% and a cell viability of 100% were obtained for dextran 3000 MW delivery using 700 pulses. For dextran 10,000 MW, the delivery efficiency was 92% and the cell viability was 98%, respectively. The device is compact, easy-to-use, and potentially applicable for cellular therapy and diagnostic purposes.

The ability to deliver foreign cargos into single living cells is of great interest in cell biology and therapeutic research. Here, we have reported a single or multiple position based nano-localized single-cell nano-electroporation platform. The device consists of an array of triangular shape ITO nano-electrodes with a 70 nm gap between two nano-electrodes, each having a 40 nm tip diameter. The voltage is applied between nano-electrodes to generate an intense electric field, which electroporates multiple nano-localized regions of the targeted single-cell membrane, and biomolecules are gently delivered into cells by pressurizing pump flow, without affecting cell viability. The platform successfully delivers dyes, QDs, and plasmids into different cell types with the variation of field strength, pulse duration, and the number of pulses. This new approach allows us to analyze delivery of different biomolecules into single living cells with high transfection efficiency (>96%, for CL1-0 cells) and high cell viability (∼98%), which are potentially beneficial for cellular therapy and diagnostic purposes.

ObjectivesElectric stimulation is used to treat a number of neurologic disorders such as epilepsy and depression. However, delivering the required current to far-field neural targets is often ineffective because of current spread through low-impedance pathways. Here, the specific aims are to develop an empirical measure for current passing through the human head and to optimize stimulation strategies for targeting deeper structures, including the auditory nerve, by utilizing the cochlear implant (CI).Materials and methodsOutward input/output (I/O) functions were obtained by CI stimulation and recording scalp potentials in five CI subjects. Conversely, inward I/O functions were obtained by noninvasive transcranial electric stimulation (tES) and recording intracochlear potentials using the onboard recording capability of the CI.ResultsI/O measures indicate substantial current spread, with a maximum of 2.2% gain recorded at the inner ear target during tES (mastoid-to-mastoid electrode configuration). Similarly, CI stimulation produced a maximum of 1.1% gain at the scalp electrode nearest the CI return electrode. Gain varied with electrode montage according to a point source model that accounted for distances between the stimulating and recording electrodes. Within the same electrode montages, current gain patterns varied across subjects suggesting the importance of tissue properties, geometry, and electrode positioning.ConclusionThese results provide a novel objective measure of electric stimulation in the human head, which can help to optimize stimulation parameters that improve neural excitation of deep structures by reducing the influence of current spread.Conflict of interestThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background To study the effects of subthalamic nucleus deep brain stimulation (STN-DBS) on autonomic dysfunction in Parkinson's disease (PD) patients. Methods 57 PD patients, who underwent bilateral STN-DBS from March to December 2018, were retrospectively analyzed, preplanned assessments at baseline and postoperatively at 1, 3 and 6 months also included the Scales for Outcomes in Parkinson's Disease-Autonomic questionnaire (SCOPA-Aut), the Unified Parkinson's Disease Rating Scale (UPDRS) III score, levodopa equivalent day dose (LEDD), Parkinson's Disease Quality of Life Scale (PDQ-39), the Hamilton Anxiety Rating Scale (HAMA), the Hamilton Depression Rating Scale (HAMD). Results The SCOPA-Aut scores improved significantly [14.59% (18.32%), 24.00% (27.05%), 22.16% (27.07%), respectively, all P P P>0.05) at 6 months after operation. SCOPA-Aut scores was positively correlated with age (r=0.428, P=0.001); The improvement rate of SCCOPA-Aut scores was positively correlated with the improvement rate of HAMA and HAMD scores (HAMA: r=0.325, P=0.015; HAMD: r=0.265, P=0.049) at 6 months after operation. Conclusion STN-DBS can improve autonomic dysfunction symptoms of PD patients, urinary and thermoregulatory subitems of autonomic dysfunction were improved in the short term after operation. There was a close relationship between improved autonomic symptoms and improved anxiety and depression 6 months after operation. We should pay more attention to the autonomic dysfunction in Parkinson's disease, detailed preoperative evaluation and postoperative follow-up, so as to better improve the QOL of patients.

Because hearing loss is a high-risk factor for cognitive decline, tinnitus, a comorbid condition of hearing loss, is often presumed to impair cognition. The present cross-sectional study aimed to delineate the interaction of tinnitus and cognition in the elderly with and without hearing loss after adjusting for covariates in race, age, sex, education, pure tone average, hearing aids, and physical well-being. Participants included 643 adults (60–69 years old; 51.3% females) from the National Health and Nutrition Examination Survey (NHANES, 2011–2012), and 1,716 (60–69 years old; 60.4% females) from the Hispanic Community Health Study (HCHS, 2008–2011). Multivariable linear and binary logistic regression was used to assess the association between tinnitus and cognition in the two sub-cohorts of normal hearing (NHANES, n = 508; HCHS, n = 1264) and hearing loss (NHANES, n = 135; HCHS, n = 453). Cognitive performance was measured as a composite z-score from four cognitive tests: The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD)-word learning, CERAD-animal fluency, CERAD-word list recall, and the digit symbol substitution test (DSST) in NHANES, and a comparable Hispanic version of these four tests in HCHS. Multivariable linear regression revealed no association between tinnitus and cognition, except for the NHANES (non-Hispanic) participants with hearing loss, where the presence of tinnitus was associated with improved cognitive performance (Mean = 0.3; 95% CI, 0.1–0.5; p, 0.018). Using the 25th percentile score of the control (i.e., normal hearing and no tinnitus) as a threshold for poor cognitive performance, the absence of tinnitus increased the risk for poor cognitive performance (OR = 5.6, 95% CI, 1.9–17.2; p, 0.002). Sensitivity analysis found a positive correlation between tinnitus duration and cognitive performance in the NHANES cohort [F(4,140), 2.6; p, 0.037]. The present study finds no evidence for the assumption that tinnitus impairs cognitive performance in the elderly. On the contrary, tinnitus is associated with improved cognitive performance in the non-Hispanic elderly with hearing loss. The present result suggests that race be considered as an important and relevant factor in the experimental design of tinnitus research. Future longitudinal and imaging studies are needed to validate the present findings and understand their mechanisms.

The importance of tele-audiology has been heightened by the current COVID-19 pandemic. The present article reviews the current state of tele-audiology practice while presenting its limitations and opportunities. Specifically, this review addresses: (1) barriers to hearing healthcare, (2) tele-audiology services, and (3) tele-audiology key issues, challenges, and future directions. Accumulating evidence suggests that tele-audiology is a viable service delivery model, as remote hearing screening, diagnostic testing, intervention, and rehabilitation can each be completed reliably and effectively. The benefits of tele-audiology include improved access to care, increased follow-up rates, and reduced travel time and costs. Still, significant logistical and technical challenges remain from ensuring a secure and robust internet connection to controlling ambient noise and meeting all state and federal licensure and reimbursement regulations. Future research and development, especially advancements in artificial intelligence, will continue to increase tele-audiology acceptance, expand remote care, and ultimately improve patient satisfaction.

Background: Biopsies play an important role in the diagnosis of intracranial lesions, and robot-assisted procedures are increasingly common in neurosurgery centers. This research investigates the diagnoses, complications, and technology yield of 700 robotic frameless intracranial stereotactic biopsies conducted with the Remebot system.Method: This research considered 700 robotic biopsies performed between 2016 and 2020 by surgeons from the Department of Functional Neurosurgery in Beijing's Tiantan Hospital. The data collected included histological diagnoses, postoperative complications, operation times, and the accuracy of robotic manipulation.Results: Among the 700 surgeries, the positive rate of the biopsies was 98.2%. The most common histological diagnoses were gliomas, which accounted for 62.7% of cases (439/700), followed by lymphoma and germinoma, which accounted for 18.7% (131/700) and 7.6% (53/700). Bleeding was found in 14 patients (2%) by post-operation computed tomography scans. A total of 29 (4.14%) patients had clinical impairments after the operation, and 9 (1.29%) experienced epilepsy during the operation. The post-biopsy mortality rate was 0.43%. Operation time—from marking the cranial point to suturing the skin—was 16.78 ± 3.31 min (range 12–26 min). The target error was 1.13 ± 0.30 mm, and the entry point error was 0.99 ± 0.24 mm.Conclusion: A robot-assisted frameless intracranial stereotactic biopsy guided by a videometric tracker is an efficient, safe, and accurate method for biopsies.

BackgroundThis work aims to assess the effectiveness and safety of robotic assistance in ventriculoperitoneal shunting and to compare the results with data from traditional surgery.MethodsWe retrospectively analyzed 60 patients who had undergone ventriculoperitoneal shunting, of which shunts were implanted using a robot in 20 patients and using traditional surgical methods in the other 40 patients. Data related to surgery were compared between the two groups, and the accuracy of the drainage tube in the robot-assisted group was assessed.ResultsIn the robot-assisted surgery group, the operation duration was 29.75 ± 6.38 min, intraoperative blood loss was 10.0 ± 3.98 ml, the success rate of a single puncture was 100%, and the bone hole diameter was 4.0 ± 0.3 mm. On the other hand, the operation duration was 48.63 ± 6.60 min, intraoperative blood loss was 22.25 ± 4.52 ml, the success rate of a single puncture was 77.5%, and the bone hole diameter was 11.0 ± 0.2 mm in the traditional surgery group. The above are statistically different between the two groups (P < 0.05). Only one case of surgery-related complications occurred in the robot-assisted group, while 13 cases occurred in the traditional surgery group. There was no significant difference in the hospitalization time. In the robot-assisted surgery group, the average radial error was 2.4 ± 1.5 mm and the average axial error was 1.9 ± 2.1 mm.ConclusionIn summary, robot-assisted implantation is accurate, simple to operate, and practical; the duration of surgery is short; trauma to the patient is reduced; and fewer postoperative complications related to surgery are reported.

Wenhui Mao and coauthors discuss possible implications of the COVID-19 pandemic for health aspirations in low- and middle-income countries.

Targeted intracellular delivery of biomolecules and therapeutic cargo enables the controlled manipulation of cellular processes. Laser-based optoporation has emerged as a versatile, non-invasive technique that employs light-based transient physical disruption of the cell membrane and achieves high transfection efficiency with low cell damage. Testing of the delivery efficiency of optoporation-based techniques has been conducted on single cells in monolayers, but its applicability in three-dimensional (3D) cell clusters/spheroids has not been explored. Cancer cells grown as 3D tumor spheroids are widely used in anti-cancer drug screening and can be potentially employed for testing delivery efficiency. Towards this goal, we demonstrated the optoporation-based high-throughput intracellular delivery of a model fluorescent cargo (propidium iodide, PI) within 3D SiHa human cervical cancer spheroids. To enable this technique, nano-spiked core–shell gold-coated polystyrene nanoparticles (ns-AuNPs) with a high surface-to-volume ratio were fabricated. ns-AuNPs exhibited high electric field enhancement and highly localized heating at an excitation wavelength of 680 nm. ns-AuNPs were co-incubated with cancer cells within hanging droplets to enable the rapid aggregation and assembly of spheroids. Nanosecond pulsed-laser excitation at the optimized values of laser fluence (45 mJ cm(−2)), pulse frequency (10 Hz), laser exposure time (30 s), and ns-AuNP concentration (5 × 10(10) particles per ml) resulted in the successful delivery of PI dye into cancer cells. This technique ensured high delivery efficiency (89.6 ± 2.8%) while maintaining high cellular viability (97.4 ± 0.4%), thereby validating the applicability of this technique for intracellular delivery. The optoporation-based strategy can enable high-throughput single cell manipulation, is scalable towards larger 3D tissue constructs, and may provide translational benefits for the delivery of anti-cancer therapeutics to tumors.

Objective: Vagus nerve stimulation (VNS) is an adjunctive and well-established treatment for patients with drug-resistant epilepsy (DRE). However, it is still difficult to identify patients who may benefit from VNS surgery. Our study aims to propose a VNS outcome prediction model based on machine learning with multidimensional preoperative heart rate variability (HRV) indices.Methods: The preoperative electrocardiography (ECG) of 59 patients with DRE and of 50 healthy controls were analyzed. Responders were defined as having at least 50% average monthly seizure frequency reduction at 1-year follow-up. Time domain, frequency domain, and non-linear indices of HRV were compared between 30 responders and 29 non-responders in awake and sleep states, respectively. For feature selection, univariate filter and recursive feature elimination (RFE) algorithms were performed to assess the importance of different HRV indices to VNS outcome prediction and improve the classification performance. Random forest (RF) was used to train the classifier, and leave-one-out (LOO) cross-validation was performed to evaluate the prediction model.Results: Among 52 HRV indices, 49 showed significant differences between DRE patients and healthy controls. In sleep state, 35 HRV indices of responders were significantly higher than those of non-responders, while 16 of them showed the same differences in awake state. Low-frequency power (LF) ranked first in the importance ranking results by univariate filter and RFE methods, respectively. With HRV indices in sleep state, our model achieved 74.6% accuracy, 80% precision, 70.6% recall, and 75% F1 for VNS outcome prediction, which was better than the optimal performance in awake state (65.3% accuracy, 66.4% precision, 70.5% recall, and 68.4% F1).Significance: With the ECG during sleep state and machine learning techniques, the statistical model based on preoperative HRV could achieve a better performance of VNS outcome prediction and, therefore, help patients who are not suitable for VNS to avoid the high cost of surgery and possible risks of long-term stimulation.

This study demonstrates a novel multi-functional microfluidic system, designated three dimensional Alternative Current Electrokinetic/Surface Enhanced Raman Scattering (3D-ACEK/SERS), which can concentrate bacteria from whole blood, identify bacterial species, and determine antibiotic susceptibilities of the bacteria rapidly. The system consists of a hybrid electrokinetic mechanism, integrating AC-electroosmosis (AC-EO) and dielectrophoresis (DEP) that allows thousand-fold concentration of bacteria, including S. aureus, Escherichia coli, and Chryseobacterium indologenes, in the center of an electrode with a wide range of working distance (hundreds to thousands of μm), while exclusion of blood cells through negative DEP forces. This microchip employs SERS assay to determine the identity of the concentrated bacteria in approximately 2 min with a limit of detection of 3 CFU/ml, 5 orders of magnitude lower than that using standard centrifugation−purification process. Finally, label-free antibiotic susceptibility testing has been successfully demonstrated on the platform using both antibiotic-sensitive and multidrug-resistant bacterial strains illustrating a potential utility of the system to clinical applications.

Electrophysiological studies show that nicotine enhances neural responses to characteristic frequency stimuli. Previous behavioral studies partially corroborate these findings in young adults, showing that nicotine selectively enhances auditory processing in difficult listening conditions. The present work extended previous work to include both young and older adults and assessed the nicotine effect on sound frequency and intensity discrimination. Hypotheses were that nicotine improves auditory performance and that the degree of improvement is inversely proportional to baseline performance. Young (19–23 years old) normal-hearing nonsmokers and elderly (61–80) nonsmokers with normal hearing between 500 and 2000 Hz received nicotine gum (6 mg) or placebo gum in a single-blind, randomized crossover design. Participants performed three experiments (frequency discrimination, frequency modulation identification, and intensity discrimination) before and after treatment. The perceptual differences were analyzed between pre- and post-treatment, as well as between post-treatment nicotine and placebo conditions as a function of pre-treatment baseline performance. Compared to pre-treatment performance, nicotine significantly improved frequency discrimination. Compared to placebo, nicotine significantly improved performance for intensity discrimination, and the improvement was more pronounced in the elderly with lower baseline performance. Nicotine had no effect on frequency modulation identification. Nicotine effects are task-dependent, reflecting possible interplays of subjects, tasks and neural mechanisms.

The ability to deliver foreign molecules into a single living cell with high transfection efficiency and high cell viability is of great interest in cell biology for applications in therapeutic development, diagnostics, and drug delivery towards personalized medicine. Various physical delivery methods have long demonstrated the ability to deliver cargo molecules directly to the cytoplasm or nucleus and the mechanisms underlying most of the approaches have been extensively investigated. However, most of these techniques are bulk approaches that are cell-specific and have low throughput delivery. In comparison to bulk measurements, single-cell measurement technologies can provide a better understanding of the interactions among molecules, organelles, cells, and the microenvironment, which can aid in the development of therapeutics and diagnostic tools. To elucidate distinct responses during cell genetic modification, methods to achieve transfection at the single-cell level are of great interest. In recent years, single-cell technologies have become increasingly robust and accessible, although limitations exist. This review article aims to cover various microfluidic-based physical methods for single-cell intracellular delivery such as electroporation, mechanoporation, microinjection, sonoporation, optoporation, magnetoporation, and thermoporation and their analysis. The mechanisms of various physical methods, their applications, limitations, and prospects are also elaborated.

Background: The Ommaya reservoir implantation technique allows for bypass of the blood-brain barrier. It can be continuously administered locally and be used to repeatedly flush the intracranial cavity to achieve the purpose of treatment. Accurate, fast, and minimally invasive placement of the drainage tube is essential during the Ommaya reservoir implantation technique, which can be achieved with the assistance of robots.Methods: We retrospectively analyzed a total of 100 patients undergoing Ommaya reservoir implantation, of which 50 were implanted using a robot, and the remaining 50 were implanted using conventional surgical methods. We then compared the data related to surgery between the two groups and calculated the accuracy of the drainage tube of the robot-assisted group.Results: The average operation time of robot-assisted surgery groups was 41.17 ± 11.09 min, the bone hole diameter was 4.1 ± 0.5 mm, the intraoperative blood loss was 11.1 ± 3.08 ml, and the average hospitalization time was 3.9 ± 1.2 days. All of the Ommaya reservoirs were successful in one pass, and there were no complications such as infection or incorrect placement of the tube. In the conventional Ommaya reservoir implantation group, the average operation time was 65 ± 14.32 min, the bone hole diameter was 11.3 ± 0.3 mm, the intraoperative blood loss was 19.9 ± 3.98 ml, and the average hospitalization time was 4.1 ± 0.5 days. In the robot-assisted surgery group, the radial error was 2.14 ± 0.99 mm and the axial error was 1.69 ± 1.24 mm.Conclusions: Robot-assisted stereotactic Ommaya reservoir implantation is quick, effective, and minimally invasive. The technique effectively negates the inefficiencies of craniotomy and provides a novel treatment for intracranial lesions.

Background The aim of this study was to summarize the clinical experience of extracorporeal cardiopulmonary resuscitation (ECPR) in the treatment of adult patients with refractory cardiac arrest. Methods The clinical data of 12 cases of adult patients with cardiac arrest hospitalized between June 2015 and September 2019 who were unable to achieve return of spontaneous circulation effectively with conventional cardiopulmonary resuscitation (CCPR) and were treated with ECPR technology were retrospectively analyzed. The group included six males and six females aged between 18 and 69 years. All the patients underwent veno-arterial extracorporeal membrane oxygenation (V-A ECMO) support with the adoption of femoral artery and vein catheterization. Results The duration of cardiopulmonary resuscitation (CPR) for the 12 patients was 32-125 min, and the ECMO duration was 2-190 h. Four patients were successfully weaned from ECMO and survived until hospital discharge. The other eight patients died in hospital; hemodynamic collapse (four patients) in the early stage of ECMO and severe neurological complications (three patients) were the main causes of death. Conclusions Single-center data showed that ECPR provided a new rescue alternative for some patients with reversible refractory cardiac arrest. We have demonstrated that the success rate of treatment could be improved by selecting suitable patients and reducing the CPR duration as much as possible.

Tourette syndrome (TS) is a childhood-onset, chronic neuropsychiatric disorder characterized by multiple motor and vocal tics. TS poses a considerable burden on both patients and health care providers, leading to a major detriment of educational success, occupation, and interpersonal relationships. A multidisciplinary, specialist-driven management approach is required due to the complexity of TS. However, access to such specialty care is often dramatically limited by the patients' locations and the specialists' geographic clustering in large urban centers. Telemedicine uses electronic information and communication technology to provide and support health care when distance separates participants. Therefore, we conducted this mini-review to describe the latest information on telemedicine in the assessment and management of TS and discuss the potential contributions to care for TS patients with a multidisciplinary approach. We believe that telemedicine could be a revolutionary method in improving medical access to patients with TS.

Tinnitus is a phantom auditory sensation in the absence of external sounds, while hyperacusis is an atypical sensitivity to external sounds that leads them to be perceived as abnormally loud or even painful. Both conditions may reflect the brain's over-compensation for reduced input from the ear. The present work differentiates between two compensation models: The additive central noise compensates for hearing loss and is likely to generate tinnitus, whereas the multiplicative central gain compensates for hidden hearing loss and is likely to generate hyperacusis. Importantly, both models predict increased variance in central representations of sounds, especially a nonlinear increase in variance by the central gain. The increased central variance limits the amount of central compensation and reduces temporal synchrony, which can explain the insufficient central gain reported in the literature. Future studies need to collect trial-by-trial firing variance data so that the present variance-based model can be falsified.

Human electromyogram (EMG) contains abundant body movement information, which is often used as the information medium of human-robot interaction. Precisely analyzing the muscle activity information contained in the patient's EMG and using it for the motion control of the rehabilitation robot is of great significance in the rehabilitation training process. Aiming at the problem that ankle rehabilitation robot needs to use the patient's EMG to identify the ankle motion intention and estimate the angle of continuous motion in the human-robot interactive rehabilitation training, this paper proposes a new method based on the patient's EMG to directly identify the type of ankle motion and estimate the continuous motion angle of the joint. Considering the nonlinear relationship between EMG and joint motion angles, Hammerstein model is selected to describe the relationship between them. The linear and nonlinear structure of the Hammerstein model simplifies the difficulty of model identification. First, obtain the real motion angle of the ankle joint while collecting the EMG of the muscles related to the ankle joint motion, and use the threshold judgment method to complete the recognition of the ankle joint motion intention. Then, use the EMG as the input of the motion model and the real motion angle of the ankle joint as the motion model output, identify and obtain the Hammerstein motion model of plantarflexion motion and dorsiflexion motion respectively. Finally, use EMG as the input of the recognized model to estimate the continuous motion angle of the ankle joint. The experiment shows that the motion model established by the method in this paper can realize the recognition of the motion intention of the ankle joint and the accurate estimation of the continuous motion angle, this method is worth promoting.

To examine difficulties experienced by cochlear implant (CI) users when perceiving non-native speech, intelligibility of non-native speech was compared in conditions with single and multiple alternating talkers. Compared to listeners with normal hearing, no rapid talker-dependent adaptation was observed and performance was approximately 40% lower for CI users following increased exposure in both talker conditions. Results suggest that lower performance for CI users may stem from combined effects of limited spectral resolution, which diminishes perceptible differences across accents, and limited access to talker-specific acoustic features of speech, which reduces the ability to adapt to non-native speech in a talker-dependent manner.

Objectives To investigate the relationship between the position of bilateral STN-DBS location of active contacts and clinical efficacy of STN-DBS in the motor symptoms of Parkinson’ disease (PD) patients. Methods We retrospectively analyzed the clinical data of 57 patients with PD who underwent bilateral STN-DBS from March 2018 to December 2018. UPDRS III scores, LEDD, PDQ-39 scores before operation and within 6 months after operation were determined. The location of activate contacts and volume of tissue activated (VTA) in the Montreal Neurological Institute (MNI) space, and their correlation with the rate of improvement of motor symptoms（UPDRS-Ⅲ score improvement rate）were examined. Results After 6 months of follow up, the UPDRS-Ⅲ scores of 57 patients（Med-off） were improved by 55.4±18.9% (P＜0.001) compared with that before operation. The improvement rate of PDQ-39 score [(47.4±23.2)%, (PPr=0.461, P＜0.001; LEDD:r=0.354, P=0.007)，the rate of improvement of UPDRS Ⅲ (Med-off) and the Z-axis coordinate of the active contact in the MNI space were positively correlated (left side:r=0.349,P=0.008;right eide:r=0.369,P=0.005). In the MNI space,there was no correlation between the UPDRS-Ⅲ score improvement rate (Med-off) at 6 months after operation and bilateral VTA in the STN motor subregion,STN associative subregion and STN limbic subregion of the active electrode contacts of 57 patients(all P>0.05).At 6 months after surgery, the difference between the Z-axis coordinate in the different improvement rate subgroups（＜25%, 25% to 50%, and＞50%） in the MNI space was statistically significant (left side: P=0.030; right side: P=0.024). In the MNI space, there was no statistically significant difference between the 3 groups in the VTA of the active electrode contacts (all P>0.05). Conclusions STN-DBS could improve the motor symptoms of PD patients and improved the quality of life. The closer the active stimulation contacts is to the dorsolateral sensorimotor area of STN, the better effect the DBS has on the motor symptoms of PD patients.

Tissue-specific microenvironmental factors contribute to the targeting preferences of metastatic cancers. However, the physical attributes of the premetastatic microenvironment are not yet fully characterized. In this research, we develop a transwell-based alginate hydrogel (TAH) model to study how permeability, stiffness, and roughness of a hanging alginate hydrogel regulate breast cancer cell homing. In this model, a layer of physically characterized alginate hydrogel is formed at the bottom of a transwell insert, which is placed into a matching culture well with an adherent monolayer of breast cancer cells. We found that breast cancer cells dissociate from the monolayer and home to the TAH for continual growth. The process is facilitated by the presence of rich serum in the upper chamber, the increased stiffness of the gel, as well as its surface roughness. This model is able to support the homing ability of MCF-7 and MDA-MB-231 cells drifting across the vertical distance in the culture medium. Cells homing to the TAH display stemness phenotype morphologically and biochemically. Taken together, these findings suggest that permeability, stiffness, and roughness are important physical factors to regulate breast cancer homing to a premetastatic microenvironment.

Tinnitus is a sound heard by 15% of the general population in the absence of any external sound. Because external sounds can sometimes mask tinnitus, tinnitus is assumed to affect the perception of external sounds, leading to hypotheses such as "tinnitus filling in the temporal gap" in animal models and "tinnitus inducing hearing difficulty" in human subjects. Here we compared performance in temporal, spectral, intensive, masking and speech-in-noise perception tasks between 45 human listeners with chronic tinnitus (18 females and 27 males with a range of ages and degrees of hearing loss) and 27 young, normal-hearing listeners without tinnitus (11 females and 16 males). After controlling for age, hearing loss, and stimulus variables, we discovered that, contradictory to the widely held assumption, tinnitus does not interfere with the perception of external sounds in 32 of the 36 measures. We interpret the present result to reflect a bottom-up pathway for the external sound and a separate top-down pathway for tinnitus. We propose that these two perceptual pathways can be independently modulated by attention, which leads to the asymmetrical interaction between external and internal sounds, and several other puzzling tinnitus phenomena such as discrepancy in loudness between tinnitus rating and matching. The present results suggest not only a need for new theories involving attention and central noise in animal tinnitus models but also a shift in focus from treating tinnitus to managing its comorbid conditions when addressing complaints about hearing difficulty in individuals with tinnitus.SIGNIFICANCE STATEMENT Tinnitus, or ringing in the ears, is a neurologic disorder that affects 15% of the general population. Here we discovered an asymmetrical relationship between tinnitus and external sounds: although external sounds have been widely used to cover up tinnitus, tinnitus does not impair, and sometimes even improves, the perception of external sounds. This counterintuitive discovery contradicts the general belief held by scientists, clinicians, and even individuals with tinnitus themselves, who often report hearing difficulty, especially in noise. We attribute the counterintuitive discovery to two independent pathways: the bottom-up perception of external sounds and the top-down perception of tinnitus. Clinically, the present work suggests a shift in focus from treating tinnitus itself to treating its comorbid conditions and secondary effects.

The brain is an intricate network with complex organizational principles facilitating a concerted communication between single-neurons, distinct neuron populations, and remote brain areas. The communication, technically referred to as connectivity, between single-neurons, is the center of many investigations aimed at elucidating pathophysiology, anatomical differences, and structural and functional features. In comparison with bulk analysis, single-neuron analysis can provide precise information about neurons or even sub-neuron level electrophysiology, anatomical differences, pathophysiology, structural and functional features, in addition to their communications with other neurons, and can promote essential information to understand the brain and its activity. This review highlights various single-neuron models and their behaviors, followed by different analysis methods. Again, to elucidate cellular dynamics in terms of electrophysiology at the single-neuron level, we emphasize in detail the role of single-neuron mapping and electrophysiological recording. We also elaborate on the recent development of single-neuron isolation, manipulation, and therapeutic progress using advanced micro/nanofluidic devices, as well as microinjection, electroporation, microelectrode array, optical transfection, optogenetic techniques. Further, the development in the field of artificial intelligence in relation to single-neurons is highlighted. The review concludes with between limitations and future prospects of single-neuron analyses.

A microfluidic chip, which can separate and enrich leukocytes from whole blood, is proposed. The chip has 10 switchback curve channels, which are connected by straight channels. The straight channels are designed to permit the inertial migration effect and to concentrate the blood cells, while the curve channels allow the Dean flow to further classify the blood cells based on the cell sizes. Hydrodynamic suction is also utilized to remove smaller blood cells (e.g., red blood cell (RBC)) in the curve channels for higher separation purity. By employing the inertial migration, Dean flow force, and hydrodynamic suction in a continuous flow system, our chip successfully separates large white blood cells (WBCs) from the whole blood with the processing rates as high as 1 &times, 108 cells/sec at a high recovery rate at 93.2% and very few RBCs (~0.1%).

RATIONALE. Electrophysiological studies show that systemic nicotine narrows frequency receptive fields and increases gain in neural responses to characteristic-frequency stimuli. We postulated that nicotine enhances related auditory processing in humans. OBJECTIVES. The main hypothesis was that nicotine improves auditory performance. A secondary hypothesis was that the degree of nicotine-induced improvement depends on the individual’s baseline performance. METHODS. Young (18–27 years old), normal-hearing, non-smokers received nicotine (Nicorette gum, 6 mg) or placebo gum in a single-blind, randomized, crossover design. Subjects performed four experiments involving tone-in-noise detection, temporal gap detection, spectral ripple discrimination and selective auditory attention before and after treatment. The perceptual differences between post-treatment nicotine and placebo conditions were measured and analyzed as a function of the pre-treatment baseline performance. RESULTS. Nicotine significantly improved performance in the more difficult tasks of tone-in-noise detection and selective attention (effect size=−0.3) but had no effect on relatively easier tasks of temporal gap detection and spectral ripple discrimination. The two tasks showing significant nicotine effects further showed no baseline-dependent improvement. CONCLUSIONS. Nicotine improves auditory performance in difficult listening situations. The present results support future investigation of nicotine effects in clinical populations with auditory processing deficits or reduced cholinergic activation.

Introduction: Deep brain stimulation (DBS) is an effective therapy for resting tremor in Parkinson's disease (PD). However, quick and objective biomarkers for quantifying the efficacy of DBS intraoperatively are lacking. Therefore, we aimed to study how DBS modulates the intraoperative neuromuscular pattern of resting tremor in PD patients and to find predictive surface electromyography (sEMG) biomarkers for quantifying the intraoperative efficacy of DBS. Methods: Intraoperative sEMG of 39 PD patients with resting tremor was measured with the DBS on and off, respectively, during the intraoperative DBS testing stage. Twelve signal features (time and frequency domains) were extracted from the intraoperative sEMG data. These sEMG features were associated with the clinical outcome to evaluate the efficacy of intraoperative DBS. Also, an sEMG-based prediction model was established to predict the clinical improvement rate (IR) of resting tremor with DBS therapy. Results: A typical resting tremor with a peak frequency of 4.93 ± 0.98 Hz (mean ± SD) was measured. Compared to the baseline, DBS modulated significant neuromuscular pattern changes in most features except for the peak frequency, by decreasing the motor unit firing rate, amplitude, or power and by changing the regularity pattern. Three sEMG features were detected with significant associations with the clinical improvement rate (IR) of the tremor scale: peak frequency power (R = 0.37, p = 0.03), weighted root mean square (R = 0.42, p = 0.01), and modified mean amplitude power (R = 0.48, p = 0.003). These were adopted to train a Gaussian process regression model with a leave-one-out cross-validation procedure. The prediction values from the trained sEMG prediction model (1,000 permutations, p = 0.003) showed a good correlation (r = 0.47, p = 0.0043) with the true IR of the tremor scale. Conclusion: DBS acutely modulated the intraoperative resting tremor, mainly by suppressing the amplitude and motor unit firing rate and by changing the regularity pattern, but not by modifying the frequency pattern. Three features showed strong robustness and could be used as quick intraoperative biomarkers to quantify and predict the efficacy of DBS in PD patients with resting tremor.

With the society’s increasingly urgent need for precision medical services [1,2], only relying on a wealth of practical experience and higher level of knowledge of medical experts and professors is limited, while the traditional diagnosis and treatment technology is limited [3]...

Background: Previousresearchessuggest that T-type Cav3.2 channels in arterial vascular smooth muscle cells (VSMCs) and caveolae have contribution on elementary Ca2+ signaling (Ca2+ sparks) via ryanodine receptors (RyRs) to cause vasodilation. RyRs are major Ca2+-release channels in the sarcoplasmic reticulum membrane of myocytes.VSMCs exhibit 3 differentisoforms of RyR (RyR1, RyR2, and RyR3).Here, we aim to elucidate the contribution of caveolar Cav3.2 channels and their functional interaction with Cav1.2 channels to trigger Ca2+ sparks in VSMCs. We also tested the hypothesis that vascular smooth muscle cell RyR2 play a specificrole in Ca2+sparks generation in VSMCs. Methods: We used tamoxifen-inducible smooth muscle-specific Cav1.2-/- (SMAKO) mice, tamoxifen-induciblesmooth muscle cell–specific RyR2-/- mice and laser scanning confocal microscopy to assess Ca2+ sparks in arterial VSMCs. Ni2+, Cd2+ and methyl-ß-cyclodextrin were used to inhibit Cav3.2 channels, Cav1.2 channels, and caveolae, respectively. Results: We found that 50 µmol/L Ni2+ and 10 mmol/Lmethyl-ß-cyclodextrindecreased Ca2+ spark frequency by ~20-30% in mesenteric artery VSMCs in a non-additive manner,but failed to inhibit Ca2+ sparks in tibial and cerebral artery VSMCs. 200 µmol/L Cd2+ suppressed Ca2+ sparks in mesenteric arteries by ~70-80%. A similar suppression of Ca2+ sparks was seen in mesenteric artery VSMCs of SMAKO mice. The remaining Ca2+ sparks were fully abolished by Ni2+ or methyl-ß-cyclodextrin. Our results demonstrate that Ca2+ influx through CaV1.2 channelsis the primary means of triggeringCa2+ sparks in murine arterial VSMCs. CaV3.2 channels, localized to caveolae and tightly coupled to RyR, provide an additional Ca2+ source for Ca2+ spark generation in mesenteric, but not tibial and cerebral arteries. In addition, targeted deletion of the RyR2 gene resulted in a complete loss of sarcoplasmic reticulum–mediated Ca2+-release events. Conclusions: Here we demonstrate that L-type CaV1.2 channels provide the predominant Ca2+ pathway for Ca2+ sparksgeneration in murine arterial VSMCs. T-type Cav3.2 channels are located in pits structures of caveolae to provide locally restricted, tight coupling between T-type Ca2+ channels and RyRs to ignite Ca2+ sparks in mesenteric arteries.Furthermore, RyR2isoform plays a dominant role in local and global VSMCs SRCa2+ release., Hintergrund: Bisherige Untersuchungen ließen vermuten, dass T-Typ CaV3.2-Kanäle in arteriellen Gefäßmuskelzellen (VSMCs) und Caveolae an elementaren Ca2+-Signalprozessen (Ca2+-Sparks) über Ryanodinrezeptoren (RyRs)zum Auslösen von Vasodilatation beteiligt sind. RyRs sind wichtige Ca2+-Freisetzungskanäle in der Membran des Sarkoplasmatischen Retikulums (SR) von Myozyten. VSMCs exprimieren 3 verschiedene Isoformen von RyR (RyR1, RyR2 und RyR3). Das Ziel dieser Studie war, den Beitrag der caveolaren CaV3.2-Kanäle und deren funktionelle Interaktion mit CaV1.2-Kanäle beim Auslösen von Ca2+-Sparks in VSMCs aufzuklären. Wir überprüften weiterhin die Hypothese, dass RyR2 in Zellen der glatten Gefäßmuskulatur eine spezifische Rolle bei der Erzeugung von Ca2+-Sparks spielen. Methoden: Wir nutzten Tamoxifen-induzierbare Glattmuskel-spezifische Cav1.2-/- (SMAKO) Mäuse, Tamoxifen-induzierbare Glattmuskel-spezifische RyR2-/--Mäuse und Laser-Scanning-Konfokalmikroskopie,um Ca2+-Sparks in VSMCs zu untersuchen. Ni2+, Cd2+und Methyl-ß-cyclodextrin wurden verwendet, um CaV3.2-Kanäle oder CaV1.2-Kanäle zu hemmenbzw. Caveolae aufzufalten. Ergebnisse: Wir haben festgestellt, dass 50 µmol/L Ni2+ und 10 mmol/L Methyl-ß-cyclodextrin die Frequenz der Ca2+-Sparks um ~20-30% in VSMCs aus Mesenterialarterien nicht-additiv verminderten, aber Ca2+-Sparks bei VSMCs aus Tibial- und Zerebralarterien nicht hemmen konnten. 200 µmol/L Cd2+unterdrückte ~70–80% der Ca2+-Sparks in VSMCs aus Mesenterialarterien. Eine ähnliche Hemmung von Ca2+-Sparks fanden wir in VSMCs aus Mesenterialarterien von SMAKO-Mäusen. Die verbliebenen Ca2+-Sparks wurden durch Ni2+ oder Methyl-ß-cyclodextrin vollständig gehemmt. Unsere Ergebnisse zeigen, dass Ca2+-Einstrom durch CaV1.2-Kanäle der Hauptweg zum Auslösen von Ca2+-Sparks in murinen arteriellen VSMCs ist. CaV3.2-Kanäle, lokalisiert in Caveolae und dicht gekoppelt an RyRs, bieten eine zusätzliche Ca2+-Einstromquelle zur Erzeugung von Ca2+-Sparks bei Mesenterial-, aber nicht bei Tibial- oder Zerebralarterien. Darüber hinaus führte die gezielte Deletion des RyR2-Genszueinemvollständigen Verlust von SR-vermitteltenCa2+-Freisetzungsereignissen. Schlussfolgerungen: Wir konnten zeigen, dass L-Typ CaV1.2-Kanäle den Haupt-Ca2+-Einstromweg zur Bildung von Ca2+-Sparks in murinen arteriellen VSMCs darstellen. T-Typ CaV3.2-Kanäle sind innerhalb von Caveolae lokalisiert, um lokal begrenztes, enges Koppeln zwischen den CaV3.2-Kanälen und RyRs zum Auslösen von Ca2+-Sparks in mesenterialarteriellen VSMCs zu ermöglichen. Außerdem spielt die RyR2-Isoform eine dominante Rolle bei der lokalen und globalen Freisetzung von VSMCs SR-Ca2+.

Psychophysical laws quantitatively relate perceptual magnitude to stimulus intensity. While most people have accepted Stevens's power function as the psychophysical law, few believe in Fechner's original idea using just-noticeable-differences (jnd) as a constant perceptual unit to educe psychophysical laws. Here I present a unified theory in hearing, starting with a general form of Zwislocki's loudness function (1965) to derive a general form of Brentano's law. I will arrive at a general form of the loudness-jnd relationship that unifies previous loudness-jnd theories. Specifically, the "slope," "proportional-jnd," and "equal-loudness, equal-jnd" theories, are three additive terms in the new unified theory. I will also show that the unified theory is consistent with empirical data in both acoustic and electric hearing. Without any free parameters, the unified theory uses loudness balance functions to successfully predict the jnd function in a wide range of hearing situations. The situations include loudness recruitment and its jnd functions in sensorineural hearing loss and simultaneous masking, loudness enhancement and the midlevel hump in forward and backward masking, abnormal loudness and jnd functions in cochlear implant subjects. Predictions of these loudness-jnd functions were thought to be questionable at best in simultaneous masking or not possible at all in forward masking. The unified theory and its successful applications suggest that although the specific form of Fechner's law needs to be revised, his original idea is valid in the wide range of hearing situations discussed here.