Cerebellar Transcranial Direct Current Stimulation Modulates Anticipatory Postural Adjustments in Healthy Adults.

During forward swinging of the arm, the central nervous system must anticipate the effect of upraising upon the body. Little is known about the cerebellar network that coordinates these anticipatory postural adjustments (APAs). Stimulating different cerebellar regions with transcranial direct current stimulation (tDCS) and with different polarities modulated the APAs. We used surface electromyography (sEMG) to measure muscle activities in a bilateral rapid shoulder flexion task. The onset of APAs was altered after tDCS over the vermis, while the postural stability and the kinematics of arm raising were not affected. To our knowledge, this is the first human cerebellar-tDCS (c-tDCS) study to separate cerebellar involvement in core muscle APAs in bilateral rapid shoulder flexion. These data contribute to our understanding of the cerebellar network supporting APAs in healthy adults. Modulated APAs of the erector spinae by tDCS on the vermis may be related to altered cerebellar brain inhibition (CBI), suggesting the importance of the vermal-cerebral connections in APAs regulation.

Effect of electrical stress on time dependent dielectric breakdown (TDDB) tolerate capability of HfO2-ZrO2ferroelectric films with different thicknesses.

HfO2-based ferroelectric materials as the most promising candidate for the ferroelectric memories, have been widely studied for more than a decade due to their excellent ferroelectric properties and CMOS compatibility. In order to realize its industrialization as soon as possible, researchers have been devoted to improving the reliability performance, such as wake up, imprint, limited endurance, et al. Among them, the breakdown characteristic is one of main failure mechanisms of HfO2-based ferroelectric devices, which limits the write/read reliability of the devices. Based on this, we systematically studied the effect of thickness on the time-dependent dielectric breakdown (TDDB) tolerate capability of HfO2-ZrO2(HZO) FE films under both forward and reverse electrical stress conditions. The thickness of HZO FE film ranged from 6 to 20 nm. Our findings reveal that decreasing the thickness of the HZO FE film leads to an improvement in TDDB tolerance capability which is attributed to the fact that higher density of oxygen vacancies in thinner HZO FE films can effectively inhibit the generation of new oxygen vacancies and the growth of conductive filaments, thus effectively improving the TDDB characteristics. These results provide a potential solution for mitigating breakdown characteristics of HfO2-based ferroelectric devices in memory applications.

Impact of multi-domain effect on the effective carrier mobility of ferroelectric field-effect transistor.

HfO2-based ferroelectric field-effect transistors (FeFETs) are a promising candidate for multilevel memory manipulation and brain-like computing due to the multi-domain properties of the HfO2FE films based polycrystalline structure. Although there have been many reports on the working mechanism of the HfO2-based FeFET and improving its reliability, the impact of multi-domain effect on the effective carrier mobility (µchannel) has not been carried out yet. The effectiveµchanneldetermines the level of readout current and affects the accuracy of the precision of peripheral circuit. In this work, FeFETs with HfZrOxFE gate dielectric were fabricated, and the effect of write (or erase) pulses with linear gradient variation on the effectiveµchannelwas studied. For the multiple downward polarization under write pulses, theµchanneldegrades as the domains gradually switch to downward. This is mainly due to the enhancement of the scattering effect induced by the positive charges (e.g. oxygen vacanciesVO2+) trapping and the increase of channel carrier density. For the erase pulses, theµchannelincreases as the domains gradually reverse to upward, which is mainly due to the reduction of the scattering effect induced by the detrapping of positive charges and the decrease of channel carrier density. In addition, the modulation effect of multilevel polarization states onµchannelis verified by numerical simulation. This effect provides a new idea and solution for the development of low power HfO2-based FeFETs in neuromorphic computing.

Programmable Bispecific Nano-immunoengager That Captures T Cells and Reprograms Tumor Microenvironment.

Immune checkpoint blockade (ICB) therapy has revolutionized clinical oncology. However, the efficacy of ICB therapy is limited by the ineffective infiltration of T effector (Teff) cells to tumors and the immunosuppressive tumor microenvironment (TME). Here, we report a programmable tumor cells/Teff cells bispecific nano-immunoengager (NIE) that can circumvent these limitations to improve ICB therapy. The peptidic nanoparticles (NIE-NPs) bind tumor cell surface α3ß1 integrin and undergo in situ transformation into nanofibrillar network nanofibers (NIE-NFs). The prolonged retained nanofibrillar network at the TME captures Teff cells via the activatable α4ß1 integrin ligand and allows sustained release of resiquimod for immunomodulation. This bispecific NIE eliminates syngeneic 4T1 breast cancer and Lewis lung cancer models in mice, when given together with anti-PD-1 antibody. The in vivo structural transformation-based supramolecular bispecific NIE represents an innovative class of programmable receptor-mediated targeted immunotherapeutics to greatly enhance ICB therapy against cancers.

Site-Specific Albumin-Selective Ligation to Human Serum Albumin under Physiological Conditions.

Human serum albumin (HSA) is the most abundant protein in human blood plasma. It plays a critical role in the native transportation of numerous drugs, metabolites, nutrients, and small molecules. HSA has been successfully used clinically as a noncovalent carrier for insulin (e.g., Levemir), GLP-1 (e.g., Liraglutide), and paclitaxel (e.g., Abraxane). Site-specific bioconjugation strategies for HSA only would greatly expand its role as the biocompatible, non-toxic platform for theranostics purposes. Using the enabling one-bead one-compound (OBOC) technology, we generated combinatorial peptide libraries containing myristic acid, a well-known binder to HSA at Sudlow I and II binding pockets, and an acrylamide. We then used HSA as a probe to screen the OBOC myristylated peptide libraries for reactive affinity elements (RAEs) that can specifically and covalently ligate to the lysine residue at the proximity of these pockets. Several RAEs have been identified and confirmed to be able to conjugate to HSA covalently. The conjugation can occur at physiological pH and proceed with a high yield within 1 h at room temperature. Tryptic peptide profiling of derivatized HSA has revealed two lysine residues (K225 and K414) as the conjugation sites, which is much more specific than the conventional lysine labeling strategy with N-hydroxysuccinimide ester. The RAE-driven site-specific ligation to HSA was found to occur even in the presence of other prevalent blood proteins such as immunoglobulin or whole serum. Furthermore, these RAEs are orthogonal to the maleimide-based conjugation strategy for Cys34 of HSA. Together, these attributes make the RAEs the promising leads to further develop in vitro and in vivo HSA bioconjugation strategies for numerous biomedical applications.

Structure-Activity Relationship of RGD-Containing Cyclic Octapeptide and αvß3 Integrin Allows for Rapid Identification of a New Peptide Antagonist.

The αvß3 integrin, a receptor for many extracellular matrix proteins with RGD-sequence motif, is involved in multiple physiological processes and highly expressed in tumor cells, therefore making it a target for cancer therapy and tumor imaging. Several RGD-containing cyclic octapeptide (named LXW analogs) were screened as αvß3 antagonists with dramatically different binding affinity, and their structure-activity relationship (SAR) remains elusive. We performed systematic SAR studies and optimized LXW analogs to improve antagonistic potency. The NMR structure of LXW64 was determined and docked to the integrin. Structural comparison and docking studies suggested that the hydrophobicity and aromaticity of the X7 amino acid are highly important for LXW analogs binding to the integrin, a potential hydrophobic pocket on the integrin surface was proposed to play a role in stabilizing the peptide binding. To develop a cost-efficient and fast screening method, computational docking was performed on LXW analogs and compared with in vitro screening. A consistency within the results of both methods was found, leading to the continuous optimization and testing of LXW mutants via in silico screening. Several new LXW analogs were predicted as the integrin antagonists, one of which-LXZ2-was validated by in vitro examination. Our study provides new insight into the RGD recognition specificity and valuable clues for rational design of novel αvß3 antagonists.

The P72R Polymorphism in R248Q/W p53 Mutants Modifies the Mutant Effect on Epithelial to Mesenchymal Transition Phenotype and Cell Invasion via CXCL1 Expression.

High-grade serous carcinoma (HGSC), the most lethal subtype of epithelial ovarian cancer (EOC), is characterized by widespread TP53 mutations (>90%), most of which are missense mutations (>70%). The objective of this study was to investigate differential transcriptional targets affected by a common germline P72R SNP (rs1042522) in two p53 hotspot mutants, R248Q and R248W, and identify the mechanism through which the P72R SNP affects the neomorphic properties of these mutants. Using isogenic cell line models, transcriptomic analysis, xenografts, and patient data, we found that the P72R SNP modifies the effect of p53 hotspot mutants on cellular morphology and invasion properties. Most importantly, RNA sequencing studies identified CXCL1 a critical factor that is differentially affected by P72R SNP in R248Q and R248W mutants and is responsible for differences in cellular morphology and functional properties observed in these p53 mutants. We show that the mutants with the P72 SNP promote a reversion of the EMT phenotype to epithelial characteristics, whereas its R72 counterpart promotes a mesenchymal transition via the chemokine CXCL1. These studies reveal a new role of the P72R SNP in modulating the neomorphic properties of p53 mutants via CXCL1, which has significant implications for tumor invasion and metastasis.

A Plug-and-Play, Drug-on-Pillar Platform for Combination Drug Screening Implemented by Microfluidic Adaptive Printing.

Traditional high-throughput drug combination screening requires automatic pipetting of drugs into high-density microtiter plates. Here, a drug-on-pillar platform is proposed for efficient combination drug screening. Using the proposed approach, combination drug screening can be carried out in a plug-and-play manner, allowing for high-throughput screening of large permutations of drug combinations at various concentrations, such that drug dispensing and cell-based screening can be temporally separated and therefore can potentially be performed at distant laboratories. The dispensing is implemented using our recently developed microfluidic pneumatic printing platform, which features a low-cost disposable cartridge that minimizes cross contamination. Moreover, our previously developed drug nanoformulation method with amphiphilic telodendrimers has been utilized to maintain drug stability in a dry form, allowing for convenient drug storage, shipping, and subsequent rehydration. Combining the features described above, we have implemented a 1260-spot drug combination array to study the effect of paired drugs against MDA-MB-231 triple negative human breast cancer cells. This study supports the feasibility of the drug-on-pillar platform for combination drug screening and has provided valuable insight into drug combination efficacy against breast cancer.

Patterning Electrospun Nanofibers via Agarose Hydrogel Stamps to Spatially Coordinate Cell Orientation in Microfluidic Device.

A straightforward, inexpensive, and reliable approach to pattern electrospun nanofibers via solvent-containing agarose hydrogel stamps is reported. Complex hierarchical microstructures can be further constructed via appropriate multistep permutation of microcontact patterning and electrospinning. As a proof-of-concept application, the patterned electrospun nanofibers are employed to spatially coordinate cell orientation in microfluidic devices.

Microfluidic-Enabled Print-to-Screen Platform for High-Throughput Screening of Combinatorial Chemotherapy.

Since the 1960s, combination chemotherapy has been widely utilized as a standard method to treat cancer. However, because of the potentially enormous number of drug candidates and combinations, conventional identification methods of the effective drug combinations are usually associated with significantly high operational costs, low throughput screening, laborious and time-consuming procedures, and ethical concerns. In this paper, we present a low-cost, high-efficiency microfluidic print-to-screen (P2S) platform, which integrates combinatorial screening with biomolecular printing for high-throughput screening of anticancer drug combinations. This P2S platform provides several distinct advantages and features, including automatic combinatorial printing, high-throughput parallel drug screening, modular disposable cartridge, and biocompatibility, which can potentially speed up the entire discovery cycle of potent drug combinations. Microfluidic impact printing utilizing plug-and-play microfluidic cartridges is experimentally characterized with controllable droplet volume and accurate positioning. Furthermore, the combinatorial print-to-screen assay is demonstrated in a proof-of-concept biological experiment which can identify the positive hits among the entire drug combination library in a parallel and rapid manner. Overall, this microfluidic print-to-screen platform offers a simple, low-cost, high-efficiency solution for high-throughput large-scale combinatorial screening and can be applicable for various emerging applications in drug cocktail discovery.

Simvastatin Overcomes Resistance to Tyrosine Kinase Inhibitors in Patient-derived, Oncogene-driven Lung Adenocarcinoma Models.

There is an unmet clinical need to develop novel strategies to overcome resistance to tyrosine kinase inhibitors (TKI) in patients with oncogene-driven lung adenocarcinoma (LUAD). The objective of this study was to determine whether simvastatin could overcome TKI resistance using the in vitro and in vivo LUAD models. Human LUAD cell lines, tumor cells, and patient-derived xenograft (PDX) models from TKI-resistant LUAD were treated with simvastatin, either alone or in combination with a matched TKI. Tumor growth inhibition was measured by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and expression of molecular targets was assessed by immunoblots. Tumors were assessed by histopathology, IHC stain, immunoblots, and RNA sequencing. We found that simvastatin had a potent antitumor effect in tested LUAD cell lines and PDX tumors, regardless of tumor genotypes. Simvastatin and TKI combination did not have antagonistic cytotoxicity in these LUAD models. In an osimertinib-resistant LUAD PDX model, simvastatin and osimertinib combination resulted in a greater reduction in tumor volume than simvastatin alone (P < 0.001). Immunoblots and IHC stain also confirmed that simvastatin inhibited TKI targets. In addition to inhibiting 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, RNA sequencing and Western blots identified the proliferation, migration, and invasion-related genes (such as PI3K/Akt/mTOR, YAP/TAZ, focal adhesion, extracellular matrix receptor), proteasome-related genes, and integrin (α3ß1, αvß3) signaling pathways as the significantly downregulated targets in these PDX tumors treated with simvastatin and a TKI. The addition of simvastatin is a safe approach to overcome acquired resistance to TKIs in several oncogene-driven LUAD models, which deserve further investigation.

Characteristics of central cortex and upper-limb flexors synchrony oxygenation during grasping in people with stroke: a controlled trial study protocol.

Background: Upper limb motor impairment is a common consequence of stroke, and the effectiveness and underlying mechanisms of rehabilitation therapy for improving upper limb function remain uncertain. Functional near-infrared spectroscopy, a reliable wearable neuroimaging technique, holds promise for investigating brain activity during functional tasks. This study aims to explore the synchronous oxygenation characteristics of the central cortex and upper-limb flexors during a grasping task and investigate the rehabilitation mechanisms of upper limb motor function in individuals with stroke. Methods: Participants with stroke who demonstrate the ability to grasp and lift cubic wood blocks of different sizes (2.5cm3, 5cm3, and 10cm3) using their affected hand will be divided into three groups: A, B, and C. Each group will consist of twenty stroke patients, resulting in a total of sixty participants with stroke. Additionally, twenty matched healthy subjects will be enrolled as a control group. Comprehensive assessments will be conducted before and after the intervention, including blood oxygen parameter monitoring of the cerebral cortex and upper limb flexors using fNIRS during the grasping task. Other assessments will include MyotonPRO, the Modified Ashworth Scale, the upper extremity section of the Fugl-Meyer Assessment, the Action Research Arm Test, and the Modified Barthel Index. The study will be undertaken between January 2024 and September 2025. Conclusions: The results of this trial will provide an in-depth understanding of the Characteristics of central cortex and upper-limb flexors synchronous oxygenation during grasping task and how it may relate to the rehabilitation mechanism of upper limb motor function in people with stroke. Clinical trial registration: https://www.chictr.org.cn, identifier ChiCTR2400080619.

Relationship between Fear-Avoidance Beliefs and Reaction Time Changes Prior to and following Exercise-Induced Muscle Fatigue in Chronic Low Back Pain.

Background: Reaction time is a reliable indicator of the velocity and efficiency of neuromuscular control and may be associated with fear-avoidance beliefs. However, the effect of exercise-induced muscle fatigue on reaction time in chronic low back pain (cLBP) and its relationship with fear-avoidance beliefs remains poorly understood. Objectives: This study aimed to reveal the relationship between fear-avoidance beliefs and reaction time changes before and after exercise-induced muscle fatigue in cLBP. Methods: Twenty-five patients with cLBP were tested by the Biering-Sorensen test (BST) to induce exhaustive muscle fatigue. Total reaction time (TRT), premotor time (PMT), and electromechanical delay (EMD) of dominated deltoid muscle were recorded by surface electromyography during the arm-raising task with visual cues before and after muscle fatigue. The mean difference (MD) of TRT (MDTRT), PMT (MDPMT), and EMD (MDEMD) was calculated from the changes before and after muscle fatigue. Fear-avoidance beliefs questionnaire (FABQ) was applied to evaluate fear-avoidance beliefs before muscle fatigue. In addition, the duration time of BST was recorded for each subject. Results: TRT and PMT of dominated deltoid muscle were prolonged after exercise-induced muscle fatigue (Z = 3.511, p < 0.001; t = 3.431, p = 0.001), while there was no statistical difference in EMD (Z = 1.029, p = 0.304). Correlation analysis showed that both the MDTRT and MDPMT were positively correlated with FABQ (r = 0.418, p = 0.042; r = 0.422, p = 0.040). Conclusions: These findings suggested that we should pay attention to both muscle fatigue-induced reaction time delay in cLBP management and the possible psychological mechanism involved in it. Furthermore, this study implied that FABQ-based psychotherapy might serve as a potential approach for cLBP treatment by improving reaction time delay. This trial is registered with ChiCTR2300074348.

HfO2-ZrO2 Ferroelectric Capacitors with Superlattice Structure: Improving Fatigue Stability, Fatigue Recovery, and Switching Speed.

HfO2-ZrO2 ferroelectric films have recently gained considerable attention from integrated circuit researchers due to their excellent ferroelectric properties over a wide doping range and low deposition temperature. In this work, different HfO2-ZrO2 superlattice (SL) FE films with varying periodicity of HfO2 (5 cycles)-ZrO2 (5 cycles) (SL5), HfO2 (10 cycles)-ZrO2 (10 cycles) (SL10), and HfO2 (15 cycles)-ZrO2 (15 cycles) (SL15) were studied systematically. The HfZrOx (HZO) alloy was used as a comparison device. The SL5 film demonstrated improved ferroelectric properties compared to the HZO film, with the 2 times remnant polarization (2Pr) values increasing from 41.4 to 48.6 µC/cm2 at an applied voltage of 3 V/10 kHz. Furthermore, the first-order reversal curve diagrams of different SL and HZO capacitors at different states (initial, wake-up, fatigue, and recovery) were measured. The SL capacitors were found to effectively suppress the diffusion of defects during P-V cycling, resulting in improved fatigue stability characteristics and fatigue recovery capability compared to the HZO capacitor. Moreover, an improved switching speed of the SL films compared to the HZO capacitor was concluded based on the inhomogeneous field mechanism (IFM) model. These results indicate that the SL structure has a high potential in future high-speed ferroelectric memory applications with excellent stability and recovery capability.

Performance improvement of a tunnel junction memristor with amorphous insulator film.

This study theoretically demonstrated the oxygen vacancy (VO2+)-based modulation of a tunneling junction memristor (TJM) with a high and tunable tunneling electroresistance (TER) ratio. The tunneling barrier height and width are modulated by the VO2+-related dipoles, and the ON and OFF-state of the device are achieved by the accumulation of VO2+ and negative charges near the semiconductor electrode, respectively. Furthemore, the TER ratio of TJMs can be tuned by varying the density of the ion dipoles (Ndipole), thicknesses of ferroelectric-like film (TFE) and SiO2 (Tox), doping concentration (Nd) of the semiconductor electrode, and the workfunction of the top electrode (TE). An optimized TER ratio can be achieved with high oxygen vacancy density, relatively thick TFE, thin Tox, small Nd, and moderate TE workfunction.

Postural Control of Patients with Low Back Pain Under Dual-Task Conditions.

Low back pain is a major global public health problem, but the current intervention effect is not ideal. A large body of previous literature suggests that patients with chronic low back pain may have abnormal postural control, which is more evident in the dual task situation. In recent years, research on postural control in patients with low back pain under dual-task conditions has gradually become a hot topic. However, the results obtained from these studies were not entirely consistent. In this review, we summarized relevant studies on the performance of postural control in patients with low back pain under dual-task conditions, analyze it from the perspective of the theoretical model of dual-task interaction, the specific research paradigm of dual task, the performance of postural control, and the related factors affecting postural control performance, etc. It was reasonable to assume that patients with low back pain might have a certain degree of abnormal postural control, and this abnormality was affected by comprehensive factors such as age, cognitive resource capacity, attention needs, complex sensorimotor integration, external environment, etc. Furthermore, postural control performance in low back pain patients under dual-task conditions was further influenced by the nature and complexity of the different tasks. In general, the more attention resources were needed, the external environmental conditions were worse, and the age-related functions were degenerate, etc., the weaker posture control ability was. In short, a deeper understanding of postural control in patients with low back pain under dual-task conditions may shed light on more references for the rehabilitation and management of low back pain, as well as some new ideas for scientific research on cognition and postural control.

Effect of Cognitive Load on Anticipatory Postural Adjustment Latency and its Relationship with Pain-Related Dysfunction in Non-specific Chronic Low Back Pain: A Cross-Sectional Study.

INTRODUCTION: This study aimed to investigate the effect of cognitive load on anticipatory postural adjustment (APA) latency in patients with non-specific chronic low back pain (NCLBP) and its relationship with pain-related functional changes. METHODS: A cross-sectional study was conducted from December 15, 2022 to January 25, 2023. Participants were divided into a healthy control group (n = 29) and an NCLBP group (n = 29). Each group was assigned a single task of rapid arm raising and a dual task of rapid arm raising combined with a cognitive load. The cognitive load task was conducted using visual conflict. The APA latency for bilateral trunk muscles was observed using electromyography. The duration of electromyography recording in each task cycle was 28 s. Pain related-functional changes were evaluated using Roland-Morris Disability Questionnaire (RMDQ) before all tasks. RESULTS: The APA latency for the right multifidus was significantly delayed in the NCLBP group [25.38, 95% confidence interval (CI) 13.41-37.35] than in the healthy control group (- 5.80, 95% CI - 19.28 to 7.68) during dual task (p = 0.0416). The APA latency for the right multifidus (25.38, 95% CI 13.41-37.35) and transverse abdominis/internal oblique (29.15, 95% CI 18.81-39.50) were significantly delayed compared with on the left side in the NCLBP group during dual task (- 3.03, 95% CI - 15.18-9.13, p = 0.0220; 3.69, 95% CI - 6.81 to 14.18, p = 0.0363). The latency delay of the right and left multifidus APA in the NCLBP group under the dual-task was positively correlated with RMDQ scores (r = 0.5560, p = 0.0017; r = 0.4010, p = 0.0311). CONCLUSIONS: Cognitive load could induce APA delay in the right trunk muscles and co-activation pattern changes in bilateral trunk muscle APA in patients with NCLBP. The APA onset delay in multifidus is positively related to pain-related daily dysfunction. Trial Registration ChiCTR2300068580 (retrospectively registered in February 23, 2023).

Discovery of specific ligands for oral squamous carcinoma to develop anti-cancer drug loaded precise targeting nanotherapeutics.

Oral squamous cell carcinoma has a low five-year survival rate, which may be due to late detection and a lack of effective tumor-specific therapies. Using a high throughput drug discovery strategy termed one-bead one-compound combinatorial library, the authors identified six compounds with high binding affinity to different human oral squamous cell carcinoma cell lines but not to normal cells. Current work is under way to develop these ligands to oral squamous cell carcinoma specific imaging probes or therapeutic agents.

Synaptic Behaviors in Ferroelectric-Like Field-Effect Transistors with Ultrathin Amorphous HfO2 Film.

We demonstrate a non-volatile field-effect transistor (NVFET) with a 3-nm amorphous HfO2 dielectric that can simulate the synaptic functions under the difference and repetition of gate voltage (VG) pulses. Under 100 ns write/erase (W/E) pulse, a memory window greater than 0.56 V and cycling endurance above 106 are obtained. The storied information as short-term plasticity (STP) in the device has a spiking post-synaptic drain current (ID) that is a response to the VG input pulse and spontaneous decay of ID. A refractory period after the stimuli is observed, during which the ID hardly varies with the VG well-emulating the bio-synapse behavior. Short-term memory to long-term memory transition, paired-pulse facilitation, and post-tetanic potentiation are realized by adjusting the VG pulse waveform and number. The experimental results indicate that the amorphous HfO2 NVFET is a potential candidate for artificial bio-synapse applications.

Comparative efficacy of transcranial magnetic stimulation on different targets in Parkinson's disease: A Bayesian network meta-analysis.

Background/Objective: The efficacy of transcranial magnetic stimulation (TMS) on Parkinson's disease (PD) varies across the stimulation targets. This study aims to estimate the effect of different TMS targets on motor symptoms in PD. Methods: A Bayesian hierarchical model was built to assess the effects across different TMS targets, and the rank probabilities and the surface under the cumulative ranking curve (SUCRA) values were calculated to determine the ranks of each target. The primary outcome was the Unified Parkinson's Disease Rating Scale part-III. Inconsistency between direct and indirect comparisons was assessed using the node-splitting method. Results: Thirty-six trials with 1,122 subjects were included for analysis. The pair-wise meta-analysis results showed that TMS could significantly improve motor symptoms in PD patients. Network meta-analysis results showed that the high-frequency stimulation over bilateral M1, bilateral DLPFC, and M1+DLPFC could significantly reduce the UPDRS-III scores compared with sham conditions. The high-frequency stimulation over both M1 and DLPFC had a more significant effect when compared with other parameters, and ranked first with the highest SCURA value. There was no significant inconsistency between direct and indirect comparisons. Conclusion: Considering all settings reported in our research, high-frequency stimulation over bilateral M1 or bilateral DLPFC has a moderate beneficial effect on the improvement of motor symptoms in PD (high confidence rating). High-frequency stimulation over M1+DLPFC has a prominent beneficial effect and appears to be the most effective TMS parameter setting for ameliorating motor symptoms of PD patients (high confidence rating).