Neurotrophin-3 facilitates stemness properties and associates with poor survival in lung cancer.

INTRODUCTION: Cancer stem cells (CSCs) shape the tumor microenvironment via neuroendocrine signaling and orchestrate drug resistance and metastasis. Cytokine antibody array demonstrated the upregulation of neurotrophin-3 (NT-3) in lung CSCs. This study aims to dissect the role of NT-3 in lung CSCs during tumor innervation. METHODS: Western blotting, quantitative reverse transcription-PCR, and flow cytometry were used to determine the expression of the NT-3 axis in lung CSCs. NT-3-knockdown and NT-3-overexpressed cells were derived lung CSCs, followed by examining the stemness gene expression, tumorsphere formation, transwell migration and invasion, drug resistance, soft agar colony formation, and in vivo tumorigenicity. Human lung cancer tissue microarray and bioinformatic databases were used to investigate the clinical relevance of NT-3 in lung cancer. RESULTS: NT-3 and its receptor tropomyosin receptor kinase C (TrkC) were augmented in lung tumorspheres. NT-3 silencing (shNT-3) suppressed the migration and anchorage-independent growth of lung cancer cells. Further, shNT-3 abolished the sphere-forming capability, chemo-drug resistance, invasion, and in vivo tumorigenicity of lung tumorspheres with a decreased expression of CSC markers. Conversely, NT-3 overexpression promoted migration and anchorage-independent growth and fueled tumorsphere formation by upregulating the expression of CSC markers. Lung cancer tissue microarray analysis revealed that NT-3 increased in patients with advanced stage, lymphatic metastasis and positively correlated with Sox2 expression. Bioinformatic databases confirmed a co-expression of NT-3/TrkC-axis and demonstrated that NT-3, NT-3/TrkC, NT-3/Sox2, and NT-3/CD133 worsen the survival of lung cancer patients. CONCLUSION: NT-3 conferred the stemness features in lung cancer during tumor innervation, which suggests that NT-3-targeting is feasible in eradicating lung CSCs.

Use of noninvasive brain stimulation and neurorehabilitation devices to enhance poststroke recovery: review of the current evidence and pitfalls.

Neurorehabilitation devices and technologies are crucial for enhancing stroke recovery. These include noninvasive brain stimulation devices that provide repetitive transcranial magnetic stimulation or transcranial direct current stimulation, which can remodulate an injured brain. Technologies such as robotics, virtual reality, and telerehabilitation are suitable add-ons or complements to physical therapy. However, the appropriate application of these devices and technologies, which target specific deficits and stages, for stroke therapy must be clarified. Accordingly, a literature review was conducted to evaluate the theoretical and practical evidence on the use of neurorehabilitation devices and technologies for stroke therapy. This narrative review provides a practical guide for the use of neurorehabilitation devices and describes the implications of use and potential integration of these devices into healthcare.

Concurrent Imaging and Clinical Study of the Efficacy of Hyaluronic Acid Injection for Knee Osteoarthritis: A Synovial Membrane Investigation with Ultrasound Imaging.

We investigated whether hyaluronic acid (HA) injections can ameliorate ultrasound-detected synovitis in knee osteoarthritis (OA). We recruited 103 patients with symptomatic knee OA and ultrasound-detected synovitis and performed two ultrasound-guided fluid drainage procedures, followed by the administration of a low-molecular-weight HA injection (2.5 mL) in the subpatellar bursa, at a 2-week interval. Knee ultrasound imaging evaluations were performed before injection (baseline) and at 1 and 6 months after the second injection and included the measurements of synovial vascularity by using color Doppler ultrasound, synovial fluid depth over the suprapatellar bursa (SF), and synovial hypertrophy (SH). Initial clinical assessments included a visual analog scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). VAS scores decreased significantly at both 1-month and 6-month evaluations (p < 0.001). WOMAC scores also significantly decreased at 1 month (p < 0.001), but not at 6 months (p = 0.23). The ultrasound parameters did not significantly change, except color Doppler grading, which tended to decrease at the 6-month evaluation (p = 0.059). Our findings revealed that two ultrasound-guided HA injections following fluid drainage improved pain and knee function but did not considerably influence imaging-detected synovitis in patients with knee OA.

Effect of noisy galvanic vestibular stimulation on dynamic posture sway under visual deprivation in patients with bilateral vestibular hypofunction.

A single-blind study to investigate the effects of noisy galvanic vestibular stimulation (nGVS) in straight walking and 2 Hz head yaw walking for healthy and bilateral vestibular hypofunction (BVH) participants in light and dark conditions. The optimal stimulation intensity for each participant was determined by calculating standing stability on a force plate while randomly applying six graded nGVS intensities (0-1000 µA). The chest-pelvic (C/P) ratio and lateral deviation of the center of mass (COM) were measured by motion capture during straight and 2 Hz head yaw walking in light and dark conditions. Participants were blinded to nGVS served randomly and imperceivably. Ten BVH patients and 16 healthy participants completed all trials. In the light condition, the COM lateral deviation significantly decreased only in straight walking (p = 0.037) with nGVS for the BVH. In the dark condition, both healthy (p = 0.026) and BVH (p = 0.017) exhibited decreased lateral deviation during nGVS. The C/P ratio decreased significantly in BVH for 2 Hz head yaw walking with nGVS (p = 0.005) in light conditions. This study demonstrated that nGVS effectively reduced walking deviations, especially in visual deprived condition for the BVH. Applying nGVS with different head rotation frequencies and light exposure levels may accelerate the rehabilitation process for patients with BVH.Clinical Trial Registration This clinical trial was prospectively registered at www.clinicaltrials.gov with the Unique identifier: NCT03554941. Date of registration: (13/06/2018).

Effect of ultrasound-detected synovitis on therapeutic efficacy of hyaluronic acid injection for symptomatic knee osteoarthritis.

OBJECTIVE: To determine whether ultrasound (US)-detected synovitis affects the therapeutic efficacy of hyaluronic acid (HA) injection for treating knee OA. METHODS: Patients with symptomatic knee OA were recruited. All the patients received HA injection two times at 2-week intervals. Clinical assessments were performed using a visual analogue scale (VAS) and the Western Ontario and McMaster Universities OA Index (WOMAC) at baseline and 1 and 6 months after treatment. Imaging evaluation was based on complete knee US examination and the Kellgren-Lawrence grading. Suprapatellar synovial fluid (SF) depth, synovial hypertrophy (SH) and vascularity were measured through US. RESULTS: In total, 137 patients who fulfilled the inclusion criteria were included in the analysis. All patients demonstrated improvement in VAS and WOMAC scores at 1 and 6 months after treatment (P < 0.001). Moreover, regression model-based analysis revealed significant associations of SF depth with the VAS and WOMAC scores in all patients. Each centimetre increase in the effusion diameter was associated with a decrease in the 1-month post-treatment VAS improvement percentage (15.26; 95% CI: 0.05, 29.5; P = 0.042) and 6-month post-treatment WOMAC improvement (37.43; 95% CI: 37.68, 50.69; P < 0.01). However, SH and vascularity were not significantly associated with VAS or WOMAC scores. CONCLUSION: Ultrasound detected suprapatellar effusion predicts reduced efficacy of HA injection in knee OA.

Noisy Galvanic Vestibular Stimulation (Stochastic Resonance) Changes Electroencephalography Activities and Postural Control in Patients with Bilateral Vestibular Hypofunction.

Patients with bilateral vestibular hypofunction (BVH) often suffer from imbalance, gait problems, and oscillopsia. Noisy galvanic vestibular stimulation (GVS), a technique that non-invasively stimulates the vestibular afferents, has been shown to enhance postural and walking stability. However, no study has investigated how it affects stability and neural activities while standing and walking with a 2 Hz head yaw turning. Herein, we investigated this issue by comparing differences in neural activities during standing and walking with a 2 Hz head turning, before and after noisy GVS. We applied zero-mean gaussian white noise signal stimulations in the mastoid processes of 10 healthy individuals and seven patients with BVH, and simultaneously recorded electroencephalography (EEG) signals with 32 channels. We analyzed the root mean square (RMS) of the center of pressure (COP) sway during 30 s of standing, utilizing AMTI force plates (Advanced Mechanical Technology Inc., Watertown, MA, USA). Head rotation quality when walking with a 2 Hz head yaw, with and without GVS, was analyzed using a VICON system (Vicon Motion Systems Ltd., Oxford, UK) to evaluate GVS effects on static and dynamic postural control. The RMS of COP sway was significantly reduced during GVS while standing, for both patients and healthy subjects. During walking, 2 Hz head yaw movements was significantly improved by noisy GVS in both groups. Accordingly, the EEG power of theta, alpha, beta, and gamma bands significantly increased in the left parietal lobe after noisy GVS during walking and standing in both groups. GVS post-stimulation effect changed EEG activities in the left and right precentral gyrus, and the right parietal lobe. After stimulation, EEG activity changes were greater in healthy subjects than in patients. Our findings reveal noisy GVS as a non-invasive therapeutic alternative to improve postural stability in patients with BVH. This novel approach provides insight to clinicians and researchers on brain activities during noisy GVS in standing and walking conditions in both healthy and BVH patients.

Care for Patients with Stroke During the COVID-19 Pandemic: Physical Therapy and Rehabilitation Suggestions for Preventing Secondary Stroke.

Infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the development of the novel 2019 coronavirus disease (COVID-19) and associated clinical symptoms, which typically presents as an upper respiratory syndrome such as pneumonia. Growing evidence indicates an increased prevalence of neurological involvement (e.g., in the form of stroke) during virus infection. COVID-19 has been suggested to be more than a lung infection because it affects the vasculature of the lungs and other organs and increases the risk of thrombosis. Patients with stroke are vulnerable to secondary events as a result not only of their poor vascular condition but also of their lack of access to rehabilitation resources. Herein, we review current knowledge regarding the pathophysiology of COVID-19, its possible association with neurological involvement, and current drug therapies. Suggestions are also offered regarding the potential for current neurorehabilitation therapies to be taught and practiced at home.

Care for patients with musculoskeletal pain during the COVID-19 pandemic: Physical therapy and rehabilitation suggestions for pain management.

Coronavirus disease 2019 has severely affected public health. Under social distancing and lockdown policies, patients with musculoskeletal pain have fewer opportunities than usual to receive routine medical care for pain management in hospitals. Therefore, we provided some suggestions for such patients to manage musculoskeletal pain and techniques that may be performed at home during this period.

Hyaluronic acid injection reduces inflammatory and apoptotic markers through modulation of AKT by repressing the oxidative status of neutrophils from osteoarthritic synovial fluid.

Hyaluronic acid (HA) injection into the osteoarthritis (OA) knee is one of the most popular treatment methods. The study aimed to determine whether HA exhibits antioxidant and antiapoptotic functions in the treatment of OA. Sixty-two outpatient patients with a diagnosis of knee OA were recruited. All patients received (HA) injections twice at a 2-week interval. Synovial fluid through sono-guided aspiration was collected for neutrophils isolation. Oxidative stress, apoptotic markers and related pathways in neutrophils were investigated. Among the oxidative stress markers, 4-hydroxynonenal (4-HNE) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) significantly decreased after HA injection, while superoxide dismutase (SOD) and catalase did not change, which indicated that HA injection had an antioxidant effect that was not through activation of antioxidant enzymes. In addition, we found that HA injection decreased p-AKT levels and decreased p-p53 and p-p38 but not p-GSK-3ß. Moreover, we confirmed that HA injection reduced proapoptotic markers through a mitochondria-dependent pathway and proinflammatory events. In vitro investigations also confirmed that HA reduced TNF-α-caused apoptosis in chondrocytes, however, this phenomenon was vanished by AKT inhibitor. Taken together, HA injection into human OA knees resulted antioxidant and antiapoptotic functions, as well as reduced inflammation, through modulation of the AKT pathway.

On the Application of Clustering and Classification Techniques to Analyze Metabolic Syndrome Severity Distribution Area and Critical Factors.

In recent years, metabolic syndrome has become one of the leading causes of death in Taiwan. This study proposes a classification and clustering method specific to the administrative regions of New Taipei City to explore the incidence and corresponding risk factors for metabolic syndrome in various geographic areas. We used integrated community health screening data and survey results obtained from people aged ≥40 years in each of the administrative regions of New Taipei City as study samples. Using a combination of Ward's method, multivariate analysis of variance, and k-means, we identified administrative regions of New Taipei City with metabolic syndrome incidences of a similar nature. Classification and regression tree methods were used to discover the key causes of metabolic syndrome in each region based on lifestyles and dietary habits. The administrative regions were divided into four groups: high-risk, slightly high-risk, normal-risk, and low-risk. The results showed that the severity of metabolic syndrome varies by region and the risk factors for metabolic syndrome vary by region. It has also been found that regions with a higher incidence of metabolic syndrome have relatively fewer medical resources.

Establishment of vestibular function multimodality platform.

BACKGROUND: The technology of using inertial measurement units (IMUs) to detect motions in different body segments has drawn enormous attention to research and industry. In our previous research, we have applied IMUs in evaluating and treating patients with vestibular hypofunction. Furthermore, according to the research, when a person's head rotates over 60° on either side in the horizontal plane, and desires to focus vision on any targets, then the function of gaze shift comes in to operation. Herein, we aimed to use IMUs to build up a system to evaluate vestibular ocular reflex (VOR) during gaze shifting maneuver. METHODS: In this study, we developed a platform, which combines the features of gaze shift and computerized dynamic visual acuity (cDVA), called the gaze shift DVA (gsDVA) platform. The gsDVA platform measures the orientations of the subject's head by IMU, and executed the evaluation according to the algorithm that was developed by us. Finally, we used the VICON system to validate the performance of gsDVA platform. RESULTS: The performance of the accuracy was 2.41° ± 1.08°, the maximal sensor error was within 4.25°, and highly correlated between our platform and VICON (p < 0.05, R = 0.99). The intraclass correlation coefficient (ICC) of between-day and within-day was 0.984 and 0.999, respectively. Furthermore, the platform not only executed the evaluation automatically but also recorded other information besides the head orientation, such as rotation speed, rotation time, reaction time, and visual acuity. CONCLUSION: In this study, we demonstrated the utility of vestibular evaluation, and this platform can help to clarify the relationship between gaze shift and VOR. This methodology is useful and can be applied efficiently to different disease groups for interactive evaluation and rehabilitation programs.

Developing a Health Risk Evaluation Method for Triple H.

The development of a health evaluation system from human-related data is an important issue in preventive medicine. Previously, most studies have focused on disease assessment and prevention in patients. However, even if certain risk factors are all within normal ranges, individuals may not necessarily be completely healthy. This study focused on healthy individuals to develop a new index to assess health risks; this index can be used for the prevention of multiple diseases in healthy people. The kernel density technique was proposed to estimate the distribution of common risk factors and to develop a health risk index. A dataset of hypertension, hyperlipidemia, and hyperglycemia (Triple H) data from the National Health Insurance Research Database in Taiwan was used to demonstrate the proposed analytical process. The results of risk factor changes after six weeks of exercise were used to calculate the health risk index. The results showed that the subjects experienced a 7.29% reduction in their health risk index after the exercise intervention. This finding demonstrates the potential impact of an important reference index on quantifying the effect of maintenance in healthy people.

Galectin-3 promotes CXCR2 to augment the stem-like property of renal cell carcinoma.

Although targeted therapy is usually the first-line treatment for advanced renal cell carcinoma (RCC), some patients can experience drug resistance. Cancer stem cells are tumour-initiating cells that play a vital role in drug resistance, metastasis and cancer relapse, while galectins (Gal) participate in tumour progression and drug resistance. However, the exact role of galectins in RCC stemness is yet unknown. In this study, we grew a subpopulation of RCC cells as tumour spheres with higher levels of stemness-related genes, such as Oct4, Sox2 and Nanog. Among the Gal family, Gal-3 in particular was highly expressed in RCC tumour spheres. To further investigate Gal-3's role in the stemness of RCC, lentivirus-mediated knockdown and overexpression of Gal-3 in RCC cells were used to examine both in vitro and in vivo tumorigenicity. We further assessed Gal-3 expression in RCC tissue microarray using immunohistochemistry. Upon suppressing Gal-3 in parental RCC cells, invasion, colony formation, sphere-forming ability, drug resistance and stemness-related gene expression were all significantly decreased. Furthermore, CXCL6, CXCL7 and CXCR2 were down-regulated in Gal-3-knockdown tumour spheres, while CXCR2 overexpression in Gal-3-knockdown RCC restored the ability of sphere formation. Gal-3 overexpression in RCC promoted both in vitro and in vivo tumorigenicity, and its expression was correlated with CXCR2 expression and tumour progression in clinical tissues. RCC patients with higher co-expressions of Gal-3 and CXCR2 demonstrated a worse survival rate. These results indicate that highly expressed Gal-3 may up-regulate CXCR2 to augment RCC stemness. Gal-3 may be a prognostic and innovative target of combined therapy for treating RCC.

Distributed Newton Methods for Deep Neural Networks.

Deep learning involves a difficult nonconvex optimization problem with a large number of weights between any two adjacent layers of a deep structure. To handle large data sets or complicated networks, distributed training is needed, but the calculation of function, gradient, and Hessian is expensive. In particular, the communication and the synchronization cost may become a bottleneck. In this letter, we focus on situations where the model is distributedly stored and propose a novel distributed Newton method for training deep neural networks. By variable and feature-wise data partitions and some careful designs, we are able to explicitly use the Jacobian matrix for matrix-vector products in the Newton method. Some techniques are incorporated to reduce the running time as well as memory consumption. First, to reduce the communication cost, we propose a diagonalization method such that an approximate Newton direction can be obtained without communication between machines. Second, we consider subsampled Gauss-Newton matrices for reducing the running time as well as the communication cost. Third, to reduce the synchronization cost, we terminate the process of finding an approximate Newton direction even though some nodes have not finished their tasks. Details of some implementation issues in distributed environments are thoroughly investigated. Experiments demonstrate that the proposed method is effective for the distributed training of deep neural networks. Compared with stochastic gradient methods, it is more robust and may give better test accuracy.

The Relationship between Postural Stability and Lower-Limb Muscle Activity Using an Entropy-Based Similarity Index.

The aim of this study is to see if the centre of pressure (COP) measurements on the postural stability can be used to represent the electromyography (EMG) measurement on the activity data of lower limb muscles. If so, the cost-effective COP data measurements can be used to indicate the level of postural stability and lower limb muscle activity. The Hilbert-Huang Transform method was used to analyse the data from the experimental designed to examine the correlation between lower-limb muscles and postural stability. We randomly selected 24 university students to participate in eight scenarios and simultaneously measured their COP and EMG signals during the experiments. The Empirical Mode Decomposition was used to identify the intrinsic-mode functions (IMF) that can distinguish between the COP and EMG at different states. Subsequently, similarity indices and synchronization analyses were used to calculate the correlation between the lower-limb muscle strength and the postural stability. The IMF5 of the COP signals and the IMF6 of the EMG signals were not significantly different and the average frequency was 0.8 Hz, with a range of 0-2 Hz. When the postural stability was poor, the COP and EMG had a high synchronization with index values within the range of 0.010-0.015. With good postural stability, the synchronization indices were between 0.006 and 0.080 and both exhibited low synchronization. The COP signals and the low frequency EMG signals were highly correlated. In conclusion, we demonstrated that the COP may provide enough information on postural stability without the EMG data.

Short-term effect of ultrasound-guided low-molecular-weight hyaluronic acid injection on clinical outcomes and imaging changes in patients with rheumatoid arthritis of the ankle and foot joints. A randomized controlled pilot trial.

To determine whether hyaluronic acid (HA) injection into rheumatoid arthritis ankles and feet can achieve improvement in foot function and reduce synovial hyper-vascularization. Forty-four patients with RA having unilateral or bilateral painful ankle and foot involvement (N = 75) were studied. All the patients were randomized to receive HA (N = 40) or lidocaine (LI) (N = 35) injection at 2-week intervals; Clinical assessments were performed using a visual analog scale (VAS) and foot function index (FFItotal) including subscales of pain (FFIpain) before injection at baseline, 4 weeks (first evaluation) and 12 weeks (secondary evaluation). Imaging evaluation based on color Doppler ultrasound (CDUS) and synovitis scores was performed simultaneously. HA injection improved the VAS score (p = .009), FFIpain (p = .041), and FFItotal (p = .032) considerably more than LI injections did at the first evaluation. The CDUS values at first evaluation (p = .005) and secondary evaluation (p < .001) decreased significantly compared with the base line values. HA injections reduced the CDUS values of more than half of the joints (54%, p = .042) while the control group exhibited no change (20%, p = .56). However, HA injection did not reduce the CDUS values more than LI injection did. Regarding the evaluation of synovial hypertrophy, no significant difference was observed between or within the groups in the synovitis scores. HA injection improved short-term foot function and pain reduction. HA injection may have a modest effect in reducing synovial hyper-vascularization. Further large-scale study is warranted to confirm this result.

Subsampled Hessian Newton Methods for Supervised Learning.

Newton methods can be applied in many supervised learning approaches. However, for large-scale data, the use of the whole Hessian matrix can be time-consuming. Recently, subsampled Newton methods have been proposed to reduce the computational time by using only a subset of data for calculating an approximation of the Hessian matrix. Unfortunately, we find that in some situations, the running speed is worse than the standard Newton method because cheaper but less accurate search directions are used. In this work, we propose some novel techniques to improve the existing subsampled Hessian Newton method. The main idea is to solve a two-dimensional subproblem per iteration to adjust the search direction to better minimize the second-order approximation of the function value. We prove the theoretical convergence of the proposed method. Experiments on logistic regression, linear SVM, maximum entropy, and deep networks indicate that our techniques significantly reduce the running time of the subsampled Hessian Newton method. The resulting algorithm becomes a compelling alternative to the standard Newton method for large-scale data classification.

Inhibitory repetitive transcranial magnetic stimulation of the contralesional premotor and primary motor cortices facilitate poststroke motor recovery.

PURPOSE: The premotor cortex plays a major role in motor planning and control, exhibiting hierarchical importance comparable to that of the primary motor cortex (M1). In this study, we compared the effects of cPMd modulation, which was achieved using inhibitory repetitive transcranial magnetic stimulation (rTMS), with those of contralesional M1 (cM1) modulation, to elucidate the roles of both regions on longitudinal motor recovery following a stroke. METHODS: Forty-four patients who had sustained hemiplegia for 3 to 12 months were randomly allocated to a cPMd group, cM1 group, or sham group and received 10 sessions of 1-Hz rTMS. The Medical Research Council (MRC) Scale, Fugl-Meyer Assessment (FMA), Wolf Motor Function Test (WMFT), and a cortical excitability test were administered pre- and post- rTMS intervention. RESULTS: cPMd modulation yielded significant improvements in MRC, FMA, and WMFT scores compared with sham stimulation and a significant effect on cortical excitability suppression equivalent to that of cM1 modulation, but engendered effects on motor improvement inferior to those of cM1 modulation. CONCLUSIONS: In patients with chronic stroke, the cPMd can fulfill a role similar to that of the cM1 in interhemispheric imbalance, which can be ameliorated by applying inhibitory rTMS to achieve substantial motor restoration.

Differential effect of conditioning sequences in coupling inhibitory/facilitatory repetitive transcranial magnetic stimulation for poststroke motor recovery.

INTRODUCTION: While neuromodulation through unihemispheric repetitive transcranial magnetic stimulation (rTMS) has shown promise for the motor recovery of stroke patients, the effectiveness of the coupling of different rTMS protocols remains unclear. AIMS: We aimed to test the long-term efficacy of this strategy with different applying sequences and to identify the electrophysiological correlates of motor improvements to the paretic hand. RESULTS: In our sham-controlled, double-blinded parallel study, 48 stroke patients (2-6 months poststroke) were randomly allocated to three groups. Group A underwent 20-session rTMS conditioning initiated with 10-session 1 Hz rTMS over the contralesional primary motor cortex (M1), followed by 10-session intermittent theta burst stimulation (iTBS) consequently over the ipsilesional M1; Group B underwent the same two paradigms but in reverse; and Group C received sham stimulation that was identical to Group A. We tested cortical excitability and motor assessments at the baseline, postpriming rTMS, postconsequent rTMS, and at 3-months follow-up. Group A manifested greater improvement than Group B in Fugl-Meyer Assessment (FMA), Wolf Motor Function testing (WMFT) score, and muscle strength (P = 0.001-0.02) post the priming rTMS. After the consequent rTMS, Group A continued to present a superior outcome than Group B in FMA (P = 0.015) and WMFT score (P = 0.008) with significant behavior-electrophysiological correlation. CONCLUSIONS: Conditioning the contralesional M1 prior to ipsilesional iTBS was found to be optimal for enhancing hand function, and this effect persisted for at least 3 months. Early modulation within 6 months poststroke rebalances interhemispheric competition and appears to be a feasible time window for rTMS intervention.