Exogenous stem cell therapy (SCT) has been recognized recently as a promising neuroregenerative strategy to augment recovery in stroke survivors. Mesenchymal stem cells (MSCs) are the primary source ...of stem cells used in the majority of both pre-clinical and clinical studies in stroke. In the absence of evidence-based guidelines on the use of SCT in stroke patients, understanding the progress of MSC research across published studies will assist researchers and clinicians in better achieving success in translating research. We conducted a systematic review on published literature using MSCs in both pre-clinical studies and clinical trials between 2008 and 2017 using the public databases PubMed and Ovid Medline, and the clinical trial registry (www.clinicaltrials.gov). A total of 78 pre-clinical studies and eight clinical studies were identified. While majority of the pre-clinical and clinical studies demonstrated statistically significant effects, the clinical significance of these findings was still unclear. Effect sizes could not be measured mainly due to reporting issues in pre-clinical studies, thus limiting our ability to compare results across studies quantitatively. The overall quality of both pre-clinical and clinical studies was sub-optimal. By conducting a systematic review of both pre-clinical and clinical studies on MSCs therapy in stroke, we assessed the quality of current evidence and identified several issues and gaps in translating animal studies to human trials. Addressing these issues and incorporating changes into future animal studies and human trials may lead to better success of stem cells-based therapeutics in the near future.
Repetitive transcranial magnetic stimulation (rTMS) has rapidly become an attractive therapeutic approach for stroke. However, the mechanisms underlying this remain elusive. This study aimed to ...investigate whether high-frequency rTMS improves functional recovery mediated by enhanced neurogenesis and activation of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) pathway and to compare the effect of conventional 20 Hz rTMS and intermittent theta burst stimulation (iTBS) on ischemic rats. Rats after rTMS were sacrificed seven and 14 days after middle cerebral artery occlusion (MCAO), following evaluation of neurological function. Neurogenesis was measured using specific markers: Ki67, Nestin, doublecortin (DCX), NeuN and glial fibrillary acidic protein (GFAP), and the expression levels of BDNF were visualized by Western blotting and RT-PCR analysis. Both high-frequency rTMS methods significantly improved neurological function and reduced infarct volume. Moreover, 20 Hz rTMS and iTBS significantly promoted neurogenesis, shown by an increase of Ki67/DCX, Ki67/Nestin, and Ki67/NeuN-positive cells in the peri-infarct striatum. These beneficial effects were accompanied by elevated protein levels of BDNF and phosphorylated-TrkB. In conclusion, high-frequency rTMS improves functional recovery possibly by enhancing neurogenesis and activating BDNF/TrkB signaling pathway and conventional 20 Hz rTMS is better than iTBS at enhancing neurogenesis in ischemic rats.
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Background: Repetitive transcranial magnetic stimulation (rTMS) has been employed for motor function rehabilitation for stroke patients, but its effects on post-stroke cognitive impairment (PSCI) ...remains controversial. Objective: To identify the effects of rTMS intervention on PSCI patients and its potential neural correlates to behavioral improvements. Methods: We recruited 34 PSCI patients for 20 sessions of 10 Hz rTMS or no-stim control treatments over the left dorsal lateral prefrontal cortex (DLPFC). Cognitive function was evaluated with the Montreal Cognitive Assessment Scale, Victoria Stroop Test, Rivermead Behaviour Memory Test and Activities of Daily Living (ADL) assessed with the Modified Barthel Index. 14 patients received functional magnetic resonance imaging scan, a useful noninvasive technique of determining how structurally segregated and functionally specialized brain area were interconnected, which was reflected by blood oxygenation level-dependent signals. The amplitude of low-frequency fluctuation (ALFF) and functional connectivity (FC) were applied as the analytical approaches, which were used to measure the resting-state brain activity and functional connection. Results: rTMS improved cognitive functions and ADLs for PSCI patients relative to patients that received no-stim control treatment. The cognitive improvements correlated to increased ALFF of the left medial prefrontal cortex, and increased FC of right medial prefrontal cortex and right ventral anterior cingulate cortex. Conclusions: 10Hz rTMS at DLPFC could improve cognitive function and quality of life for PSCI patients, which is associated with an altered frontal cortical activity.
Robot-assisted rehabilitation is a growing field that can provide an intensity, quality, and quantity of treatment that exceed therapist-mediated rehabilitation. Several control algorithms have been ...implemented in rehabilitation robots to develop a patient-cooperative strategy with the capacity to understand the intention of the user and provide suitable rehabilitation training. In this paper, we present an upper-limb motion pattern recognition method using surface electromyography (sEMG) signals with a support vector machine (SVM) to control a rehabilitation robot, ReRobot, which was built to conduct upper-limb rehabilitation training for post-stroke patients. For poststroke rehabilitation training using the ReRobot, the upper-limb motion of the patient's healthy side is first recognized by detecting and processing the sEMG signals; then, the ReRobot assists the impaired arm in conducting mirror rehabilitation therapy. To train and test the SVM model, five healthy subjects participated in the experiments and performed five standard upper-limb motions, including shoulder flexion, abduction, internal rotation, external rotation, and elbow joint flexion. Good accuracy was demonstrated in experimental results from the five healthy subjects. By recognizing the model motion of the healthy side, the rehabilitation robot can provide mirror therapy to the affected side. This method can be used as a control strategy of upper-limb rehabilitation robots for self-rehabilitation training with stroke patients.
Compensations are commonly observed in patients with stroke when they engage in reaching without supervision; these behaviors may be detrimental to long-term functional improvement. Automatic ...detection and reduction of compensation cab help patients perform tasks correctly and promote better upper extremity recovery.
Our first objective is to verify the feasibility of detecting compensation online using machine learning methods and pressure distribution data. Second objective was to investigate whether compensations of stroke survivors can be reduced by audiovisual or force feedback. The third objective was to compare the effectiveness of audiovisual and force feedback in reducing compensation.
Eight patients with stroke performed reaching tasks while pressure distribution data were recorded. Both the offline and online recognition accuracy were investigated to assess the feasibility of applying a support vector machine (SVM) based compensation detection system. During reduction of compensation, audiovisual feedback was delivered using virtual reality technology, and force feedback was delivered through a rehabilitation robot.
Good classification performance was obtained in online compensation recognition, with an average F1-score of over 0.95. Based on accurate online detection, real-time feedback significantly decreased compensations of patients with stroke in comparison with no-feedback condition (p < 0.001). Meanwhile, the difference between audiovisual and force feedback was also significant (p < 0.001) and force feedback was more effective in reducing compensation in patients with stroke.
Accurate online recognition validated the feasibility of monitoring compensations using machine learning algorithms and pressure distribution data. Reliable online detection also paved the way for reducing compensations by providing feedback to patients with stroke. Our findings suggested that real-time feedback could be an effective approach to reducing compensatory patterns and force feedback demonstrated a more enviable potential compared with audiovisual feedback.
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Compensatory movements are commonly employed by stroke survivors during seated reaching and may have negative effects on their long-term recovery. Detecting compensation is useful for coaching the ...patient to reduce compensatory trunk movements and improving the motor function of the paretic arm. Sensor-based and camera-based systems have been developed to detect compensatory movements, but they still have some limitations, such as causing object obstructions, requiring complex setups and raising privacy concerns. To overcome these drawbacks, this paper proposes a compensatory movement detection system based on pressure distribution data and is unobtrusive, simple and practical. Machine learning algorithms were applied to classify compensatory movements automatically. Therefore, the purpose of this study was to develop and test a pressure distribution-based system for the automatic detection of compensation movements of stroke survivors using machine learning algorithms.
Eight stroke survivors performed three types of reaching tasks (back-and-forth, side-to-side, and up-and-down reaching tasks) with both the healthy side and the affected side. The pressure distribution data were recorded, and five features were extracted for classification. The k-nearest neighbor (k-NN) and support vector machine (SVM) algorithms were applied to detect and categorize the compensatory movements. The surface electromyography (sEMG) signals of nine trunk muscles were acquired to provide a detailed description and explanation of compensatory movements.
Cross-validation yielded high classification accuracies (F1-score>0.95) for both the k-NN and SVM classifiers in detecting compensation movements during all the reaching tasks. In detail, an excellent performance was achieved in discriminating between compensation and noncompensation (NC) movements, with an average F1-score of 0.993. For the multiclass classification of compensatory movement patterns, an average F1-score of 0.981 was achieved in recognizing the NC, trunk lean-forward (TLF), trunk rotation (TR) and shoulder elevation (SE) movements.
Good classification performance in detecting and categorizing compensatory movements validated the feasibility of the proposed pressure distribution-based system. Reliable classification accuracy achieved by the machine learning algorithms indicated the potential to monitor compensation movements automatically by using the pressure distribution-based system when stroke survivors perform seated reaching tasks.
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Stroke patients often use trunk to compensate for impaired upper limb motor function during upper limb rehabilitation training, which results in a reduced rehabilitation training effect. Detecting ...trunk compensations can improve the effect of rehabilitation training. This study investigates the feasibility of a surface electromyography-based trunk compensation detection (sEMG-bTCD) method. Five healthy subjects and nine stroke subjects with cognitive and comprehension skills were recruited to participate in the experiments. The sEMG signals from nine superficial trunk muscles were collected during three rehabilitation training tasks (reach-forward-back, reach-side-to-side, and reach-up-to-down motions) without compensation and with three common trunk compensations lean-forward (LF), trunk rotation (TR), and shoulder elevation (SE). Preprocessing like filtering, active segment detection was performed and five time domain features (root mean square, variance, mean absolute value (MAV), waveform length, and the fourth order autoregressive model coefficient) were extracted from the collected sEMG signals. Excellent TCD performance was achieved in healthy participants by using support vector machine (SVM) classifier (LF: accuracy = 94.0%, AUC = 0.97, F1 = 0.94; TR: accuracy = 95.8%, AUC = 0.99, F1 = 0.96; SE: accuracy = 100.0%, AUC = 1.00, F1 = 1.00). By using SVM classifier, TCD performance in stroke participants was also obtained (LF: accuracy = 74.8%, AUC = 0.90, F1 = 0.73; TR: accuracy = 67.1%, AUC = 0.85, F1 = 0.71; SE: accuracy = 91.3%, AUC = 0.98, F1 = 0.90). Compared with the methods based on cameras or inertial sensors, better detection performance was obtained in both healthy and stroke participants. The results demonstrated the feasibility of the sEMG-bTCD method, and it helps to prompt the stroke patients to correct their incorrect posture, thereby improving the effectiveness of rehabilitation training.
Physical exercise is beneficial to the structural and functional recovery of post-ischemic stroke, but its molecular mechanism remains obscure. Herein, we aimed to explore the underlying mechanism of ...exercise-induced neuroprotection from the perspective of microRNAs (miRNAs). Adult male Sprague–Dawley (SD) rats were randomly distributed into 4 groups, i.e., the physical exercise group with the transient middle cerebral artery occlusion (tMCAO) surgery (PE-IS, n = 28); the physical exercise group without tMCAO surgery (PE, n = 6); the sedentary group with tMCAO surgery (Sed-IS, n = 28); and the sedentary group without tMCAO surgery (Sed, n = 6). Notably, rats in the PE-IS and PE groups were subjected to a running exercise for 28 days while rats in the Sed-IS and Sed groups received no exercise training. After long-term exercise, exosomal miRNAs of cerebrospinal fluid (CSF) were analyzed using high-throughput sequencing. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were employed for the differentially expressed miRNAs. Physical exercise improved the neurological function and attenuated the lesion expansion after stroke. In total, 41 differentially expressed miRNAs were screened for the GO and KEGG analysis. GO enriched terms were associated with the central nervous system, including cellular response to retinoic acid, vagus nerve morphogenesis, cellular response to hypoxia, dendritic cell chemotaxis, cell differentiation, and regulation of neuron death. Besides, these differentially expressed miRNAs were linked to the pathophysiological process of stroke, including axon guidance, NF-kappa B signaling pathway, thiamine metabolism, and MAPK signaling pathway according to KEGG analysis. In summary, exercise training significantly alleviated the neurological damage at both functional and structural levels. Moreover, the differentially expressed miRNAs regulating multiple signal pathways were potentially involved in the neuroprotective effects of physical exercise. Therefore, these miRNAs altered by physical exercise might represent the therapeutic strategy for cerebral ischemia.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The repair of white matter injury is of significant importance for functional recovery after ischemic stroke, and the up-regulation of triggering receptors expressed on myeloid cells 2 (TREM2) after ...ischemic stroke is neuroprotective and implicated in remyelination. However, the lack of effective therapies calls for the need to investigate the regenerative process of remyelination and the role of rehabilitation therapy. This study sought to investigate whether and how moderate physical exercise (PE) promotes oligodendrogenesis and remyelination in rats with transient middle cerebral artery occlusion (tMCAO).
Male Sprague-Dawley rats (weighing 250-280 g) were subjected to tMCAO. AAV-shRNA was injected into the lateral ventricle to silence the Trem2 gene before the operation. The rats in the physical exercise group started electric running cage training at 48 h after the operation. The Morris water maze and novel object recognition test were used to evaluate cognitive function. Luxol fast blue staining, diffusion tensor imaging, and electron microscopy were used to observe myelin injury and repair. Immunofluorescence staining was applied to observe the proliferation and differentiation of oligodendrocyte precursor cells (OPCs). Expression of key molecules were detected using immunofluorescence staining, quantitative real-time polymerase chain reaction, Western blotting, and Enzyme-linked immunosorbent assay, respectively.
PE exerted neuroprotective efects by modulating microglial state, promoting remyelination and recovery of neurological function of rats over 35 d after stroke, while silencing Trem2 expression in rats suppressed the aforementioned effects promoted by PE. In addition, by leveraging the activin-A neutralizing antibody, we found a direct beneficial effect of PE on microglia-derived activin-A and its subsequent role on oligodendrocyte differentiation and remyelination mediated by the activin-A/Acvr axis.
The present study reveals a novel regenerative role of PE in white matter injury after stroke, which is mediated by upregulation of TREM2 and microglia-derived factor for oligodendrocytes regeneration. PE is an effective therapeutic approach for improving white matter integrity and alleviating neurological function deficits after ischemic stroke.
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