Efficacy and Safety of Repetitive Transcranial Magnetic Stimulation in Cerebellar Ataxia: a Systematic Review and Meta-analysis.

Cerebellar ataxia(CA) is defined as a degenerative disease of the nervous system. Repetitive transcranial magnetic stimulation (rTMS) has been a promising treatment for neurological and psychiatric diseases. Hence, to find out whether cerebellar rTMS impacts CA as a potential therapy, we performed a systematic review and meta-analysis. Qualified studies through a systematic search were retrieved for randomized controlled trials (RCTs) using acknowledged databases. Review Manager 5.4 software was employed to synthesize the data. A total of seven studies were identified as eligible and included in the quantitative review. Comparing real and sham-rTMS interventions, the utilization of rTMS on cerebellum improved the scale for the assessment and rating of ataxia (SARA) (SMD - 0.87, 95% CI - 1.41 to - 0.34; P = 0.001; I2 = 62%), the International Cooperative Ataxia Rating Scale (ICARS) (SMD - 1.06, 95% CI - 1.47 to - 0.64; P < 0.00001; I2 = 0%) and Berg balance Scale (BBS) (SMD 0.76, 95% CI 0.33 to 1.19; P = 0.0005; I2 = 39%). The subgroup analysis demonstrated high-frequency of rTMS had a positive effect (SMD - 1.28, 95% CI - 1.82 to - 0.74; P < 0.00001; I2 = 0%). For the safety, the incidence of adverse events between the two groups was not significantly different (OR 1.73, 95% CI 0.55 to 5.46; P = 0.35; I2 = 0%). In conclusion, this meta-analysis provided limited evidence, suggesting a possible strategy that rTMS over the cerebellum could be a viable therapy for symptoms associated with CA. Besides, rTMS intervention was well-attended and did not result in unanticipated negative effects.

Inhibitory interaction of flavonoids with organic anion transporter 3 and their structure-activity relationships for predicting nephroprotective effects.

The organic anion transporter 3 (OAT3), an important renal uptake transporter, is associated with drug-induced acute kidney injury (AKI). Screening and identifying potent OAT3 inhibitors with little toxicity in natural products, especially flavonoids, in reducing OAT3-mediated AKI is of great value. The five strongest OAT3 inhibitors from the 97 flavonoids markedly decreased aristolochic acid I-induced cytotoxicity and alleviated methotrexate-induced nephrotoxicity. The pharmacophore model clarified hydrogen bond acceptors and hydrophobic groups are the critical pharmacophores. These findings would provide valuable information in predicting the potential risks of flavonoid-containing food/herb-drug interactions and optimizing flavonoid structure to alleviate OAT3-related AKI.

Bibliometric and visualised analysis on non-invasive cerebellar stimulation from 1995 to 2021.

Background: The non-invasive cerebellar stimulation (NICS) is a neural modulation technique, which shows the therapeutic and diagnostic potentials for rehabilitating brain functions in neurological or psychiatric diseases. There is a rapid growth in the clinical research related to NICS in recent years. Hence, we applied a bibliometric approach to analyze the current status, the hot spots, and the trends of NICS visually and systematically. Methods: We searched the NICS publications from the Web of Science (Wos) between 1995 and 2021. Both VOSviewer (1.6.18) and Citespace (Version 6.1.2) software were used to generate the co-occurrence or co-cited network maps about the authors, institutions, countries, journals, and keywords. Results: A total of 710 articles were identified in accordance with our inclusion criteria. The linear regression analysis shows a statistical increase in the number of publications per year on NICS research over time (p < 0.001). The Italy and University College London ranked the first in this field with 182 and 33 publications, respectively. Koch, Giacomo was the most prolific author (36 papers). The journal of Cerebellum, Brain stimulation and Clinical neurophysiology were the most three productive journals to publish NICS-related articles. Conclusion: Our findings provide the useful information regarding to the global trends and frontiers in NICS field. Hot topic was focused on the interaction between the transcranial direct current stimulation and functional connectivity in the brain. It could guide the future research and clinical application of NICS.

Effectiveness of cerebellar vermis intermittent theta-burst stimulation in improving trunk control and balance function for patients with subacute stroke: a randomised controlled trial protocol.

INTRODUCTION: Balance impairments frequently occur after stroke. Achieving effective core trunk stability is the key to improving balance ability. However, there is still a lack of advanced well-defined rehabilitation protocols for balance improvement in patients with stroke. Intermittent theta-burst stimulation (iTBS) is a non-invasive brain activity modulation strategy that can produce long-term potentiation. The cerebellar vermis is a fundamental structure involved in balance and motor control. However, no study has demonstrated the therapeutic effect and potential mechanism of cerebellar vermis iTBS on balance after stroke. METHODS AND ANALYSIS: This study will be a prospective single-centre double-blind randomised controlled clinical trial with a 3-week intervention and 3-week follow-up. Eligible participants will be randomly allocated to the experimental group or the control group in a 1:1 ratio. After routine conventional physical therapy, patients in the experimental group will receive cerebellar vermis iTBS, whereas patients in the control group will receive sham stimulation. The overall intervention period will be 5 days a week for 3 consecutive weeks. The outcomes will be measured at baseline (T0), 3 weeks postintervention (T1) and at the 3-week follow-up (T2). The primary outcomes are Berg Balance Scale and Trunk Impairment Scale scores. The secondary outcomes are balance test scores via the Balance Master system, muscle activation of the trunk and lower limbs via the surface electromyography recordings, cerebral cortex oxygen concentrations measured via the resting-state functional near-infrared spectroscopy, Fugl-Meyer Assessment of Lower Extremity and Barthel index scores. ETHICS AND DISSEMINATION: This study was approved by the West China Hospital Clinical Trials and Biomedical Ethics Committee of Sichuan University. All participants will sign the informed consent form voluntarily. The results of this study will be published in peer-reviewed journals and disseminated at academic conferences. TRIAL REGISTRATION NUMBER: ChiCTR2200065369.

Virtual reality for neurorehabilitation: A bibliometric analysis of knowledge structure and theme trends.

Background: As an emerging technology, virtual reality (VR) has been broadly applied in the medical field, especially in neurorehabilitation. The growing application of VR therapy promotes an increasing amount of clinical studies. In this paper, we present a bibliometric analysis of the existing studies to reveal the current research hotspots and guide future research directions. Methods: Articles and reviews on the related topic were retrieved from the Science Citation Index Expanded of Web of Science Core Collection database. VOSviewer and Citespace software were applied to systematically analyze information about publications, countries, institutions, authors, journals, citations, and keywords from the included studies. Results: A total of 1,556 papers published between 1995 and 2021 were identified. The annual number of papers increased gradually over the past three decades, with a peak publication year in 2021 (n = 276). Countries and institutions from North America and Western European were playing leading roles in publications and total citations. Current hotspots were focused on the effectiveness of VR therapy in cognitive and upper limb motor rehabilitation. The clusters of keywords contained the four targeted neurological diseases of VR, while the burst keywords represented that the latest studies were directed toward more defined types of VR therapy and greater study design. Conclusions: Our study offers information regarding to the current hotspots and emerging trends in the VR for rehabilitation field. It could guide future research and application of VR therapy in neurorehabilitation.

Post COVID-19 organizing pneumonia treated with mycophenolate mofetil.

Organizing pneumonia (OP) promptly responds to corticosteroids. However, a minority of patients demonstrate corticosteroid resistance or relapse on corticosteroid tapering. We describe post COVID-19 OP patients with clinically inadequate response to corticosteroids but that improved after the addition of Mycophenolate Mofetil (MMF). Case 1: A gentleman was diagnosed with post COVID-19 OP but had suboptimal clinico-physiologic-radiologic response and steroid toxicity during outpatient reviews. MMF was initiated resulting in marked clinical response and quick weaning from corticosteroids. Case 2: A gentleman with post COVID-19 OP relapsed during tapering of steroids. Clarithromycin and MMF were added to his regimen, which improved his clinico-physiologic parameters and allowed corticosteroid tapering. Unfortunately, he developed MMF-related colitis needing therapy cessation. Currently, no studies have reported on MMF utilization in difficult post COVID-19 OP patients. Nevertheless, we believe, similar as in non-COVID OPs, MMF or other immunomodulators, potentially have a role in treating difficult or steroid-resistant OPs.

The Immediate Effects of Intermittent Theta Burst Stimulation of the Cerebellar Vermis on Cerebral Cortical Excitability During a Balance Task in Healthy Individuals: A Pilot Study.

Objective: This pilot study aimed to investigate the immediate effects of single-session intermittent theta-burst stimulation (iTBS) on the cerebellar vermis during a balance task, which could unveil the changes of cerebral cortical excitability in healthy individuals. Subjects: A total of seven right-handed healthy subjects (26.86 ± 5.30 years) were included in this study. Interventions: Each subject received single-session iTBS on cerebellar vermis in a sitting position. Main Measures: Before and after the intervention, all subjects were asked to repeat the balance task of standing on the left leg three times. Each task consisted of 15 s of standing and 20 s of resting. Real-time changes in cerebral cortex oxygen concentrations were monitored with functional near-infrared spectroscopy (fNIRS). During the task, changes in blood oxygen concentration were recorded and converted into the mean HbO2 for statistical analysis. Results: After stimulation, the mean HbO2 in the left SMA (P = 0.029) and right SMA (P = 0.043) significantly increased compared with baseline. However, no significant changes of mean HbO2 were found in the bilateral dorsolateral prefrontal lobe (P > 0.05). Conclusion: Single-session iTBS on the cerebellar vermis in healthy adults can increase the excitability of the cerebral cortex in the bilateral supplementary motor areas during balance tasks. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [ChiCTR2100048915].

Cerebellar Intermittent Theta-Burst Stimulation Reduces Upper Limb Spasticity After Subacute Stroke: A Randomized Controlled Trial.

Objective: This study aims to explore the efficacy of cerebellar intermittent theta-burst stimulation (iTBS) on upper limb spasticity in subacute stroke patients. Methods: A total of 32 patients with upper limb spasticity were enrolled and randomly assigned to treatment with cerebellar iTBS or sham stimulation before conventional physical therapy daily for 2 weeks. The primary outcomes included the modified Ashworth scale (MAS), the modified Tardieu scale (MTS), and the shear wave velocity (SWV). The secondary outcomes were the H-maximum wave/M-maximum wave amplitude ratio (Hmax/Mmax ratio), motor-evoked potential (MEP) latency and amplitude, central motor conduction time (CMCT), and the Barthel Index (BI). All outcomes were evaluated at baseline and after 10 sessions of intervention. Results: After the intervention, both groups showed significant improvements in the MAS, MTS, SWV, and BI. In addition, patients treated with cerebellar iTBS had a significant increase in MEP amplitude, and patients treated with sham stimulation had a significant decrease in Hmax/Mmax ratio. Compared with the sham stimulation group, the MAS, MTS, and SWV decreased more in the cerebellar iTBS group. Conclusion: Cerebellar iTBS is a promising adjuvant tool to reinforce the therapeutic effect of conventional physical therapy in upper limb spasticity management after subacute stroke (Chinese Clinical Trial Registry: ChiCTR1900026516).

Cerebellar Theta Burst Stimulation on Walking Function in Stroke Patients: A Randomized Clinical Trial.

Objectives: The objective of this study was to explore the efficacy of cerebellar intermittent theta burst stimulation (iTBS) on the walking function of stroke patients. Methods: Stroke patients with walking dysfunction aged 25-80 years who had suffered their first unilateral stroke were included. A total of 36 patients [mean (SD) age, 53 (7.93) years; 10 women (28%)] were enrolled in the study. All participants received the same conventional physical therapy, including transfer, balance, and ambulation training, during admission for 50 min per day during 2 weeks (10 sessions). Every session was preceded by 3 min procedure of cerebellar iTBS applyed over the contralesional cerebellum in the intervention group or by a similar sham iTBS in control group. The groups were formed randomly and the baseline characteristics showed no significant difference. The primary outcome measure was Fugl-Meyer Assessment-Lower Extremity scores. Secondary outcomes included walking performance and corticospinal excitability. Measures were performed before the intervention beginning (T0), after the first (T1) and the second (T2) weeks. Results: The Fugl-Meyer Assessment for lower extremity scores slightly improved with time in both groups with no significant difference between the groups and over the time. The walking performance significantly improved with time and between group. Two-way mixed measures ANOVA showed that there was significant interaction between time and group in comfortable walking time (F 2,68 = 6.5242, P = 0.0080, η2 partial = 0.276, ε = 0.641), between-group comparisons revealed significant differences at T1 (P = 0.0072) and T2 (P = 0.0133). The statistical analysis of maximum walking time showed that there was significant interaction between time and groups (F 2,68 = 5.4354, P = 0.0115, η2 partial = 0.198, ε = 0.734). Compared with T0, the differences of maximum walking time between the two groups at T1 (P = 0.0227) and T2 (P = 0.0127) were statistically significant. However, both the Timed up and go test and functional ambulation category scale did not yield significant differences between groups (P > 0.05). Conclusion: Our results revealed that applying iTBS over the contralesional cerebellum paired with physical therapy could improve walking performance in patients after stroke, implying that cerebellar iTBS intervention may be a noninvasive strategy to promote walking function in these patients. This study was registered at ChiCTR, number ChiCTR1900026450.

Repetitive transcranial magnetic stimulation for lower extremity motor function in patients with stroke: a systematic review and network meta-analysis.

Transcranial magnetic stimulation, a type of noninvasive brain stimulation, has become an ancillary therapy for motor function rehabilitation. Most previous studies have focused on the effects of repetitive transcranial magnetic stimulation (rTMS) on motor function in stroke patients. There have been relatively few studies on the effects of different modalities of rTMS on lower extremity motor function and corticospinal excitability in patients with stroke. The MEDLINE, Embase, Cochrane Library, ISI Science Citation Index, Physiotherapy Evidence Database, China National Knowledge Infrastructure Library, and ClinicalTrials.gov databases were searched. Parallel or crossover randomized controlled trials that addressed the effectiveness of rTMS in patients with stroke, published from inception to November 28, 2019, were included. Standard pairwise meta-analysis was conducted using R version 3.6.1 with the "meta" package. Bayesian network analysis using the Markov chain Monte Carlo algorithm was conducted to investigate the effectiveness of different rTMS protocol interventions. Network meta-analysis results of 18 randomized controlled trials regarding lower extremity motor function recovery revealed that low-frequency rTMS had better efficacy in promoting lower extremity motor function recovery than sham stimulation. Network meta-analysis results of five randomized controlled trials demonstrated that high-frequency rTMS led to higher amplitudes of motor evoked potentials than low-frequency rTMS or sham stimulation. These findings suggest that rTMS can improve motor function in patients with stroke, and that low-frequency rTMS mainly affects motor function, whereas high-frequency rTMS increases the amplitudes of motor evoked potentials. More high-quality randomized controlled trials are needed to validate this conclusion. The work was registered in PROSPERO (registration No. CRD42020147055) on April 28, 2020.