Chronic Stroke Treatment Research Articles

386 Stereotactic Implantation of Autologous Mesenchymal Stem Cells Improves Neurological Outcomes in a Rat Model of Chronic Middle Cerebral Artery Stroke

INTRODUCTION: Limited treatment options exist for patients with chronic infarcts. Multipotent adult mesenchymal stem cells (MSC) show promise as a treatment for chronic stroke. Allogeneic MSCs have been implanted successfully in chronic stroke1,2. However, no literature evaluates the use of autologous MSCs delivered via stereotactic implantation. Autologous MSCs provide safety and accessibility benefits. METHODS: Male Sprague-Dawley rats underwent transient right MCAO for 120 minutes. Brain MRI and sensorimotor behavior were used to evaluate stroke. Sixteen days post stroke, tibial bone marrow was aspirated and MSCs were grown in a closed bioreactor. At 28 days post stroke, 3 trajectories of MSCs were implanted in the peri-infarct zone using a stereotactic robot. The treatments consisted of group 1 (5 x 106 cell dose, N = 6), group 2 (1 x 106 cell dose, N = 6) and a control group (saline injection, N = 9). In a second cohort of animals, Q-dot labeled autologous MSCs were tracked in the brain for 7 or 30 days. RESULTS: Behavior as determined by the modified neurological severity score (0-16) significantly improved in both groups. Stroke volume did not decrease. Histological analysis confirmed increased astrocyte and microglia presence in the affected hemisphere. Quantum dot analysis of injections showed presence of MSCs along trajectory as well as targeting perilesional brain tissue at 7 and 30 days post-implantation. CONCLUSIONS: Stereotactic injection of autologous MSCs represent an effective treatment for chronic stroke. Cells were effective at the lowest dose studied, with no added benefit at higher cell dosages. Unlike allogeneic MSCs which disappear over days to weeks3, autologous MSCs persist long term in the brain, potentially providing continued benefit. This treatment warrants human trials to study its effectiveness.

Magnetothermal-based non-invasive focused magnetic stimulation for functional recovery in chronic stroke treatment

Magnetic heat-based brain stimulation of specific lesions could promote the restoration of impaired motor function caused by chronic stroke. We delivered localized stimulation by nanoparticle-mediated heat generation within the targeted brain area via focused magnetic stimulation. The middle cerebral artery occlusion model was prepared, and functional recovery in the chronic-phase stroke rat model was demonstrated by the therapeutic application of focused magnetic stimulation. We observed a transient increase in blood–brain barrier permeability at the target site of < 4 mm and metabolic brain activation at the target lesion. After focused magnetic stimulation, the rotarod score increased by 390 ± 28% (p < 0.05) compared to the control group. Standardized uptake value in the focused magnetic stimulation group increased by 2063 ± 748% (p < 0.01) compared to the control group. Moreover, an increase by 24 ± 5% (p < 0.05) was observed in the sham group as well. Our results show that non-invasive focused magnetic stimulation can safely modulate BBB permeability and enhance neural activation for chronic-phase stroke treatment in the targeted deep brain area.

Abstract TP234: Delayed Administration Of A Repurposed Drug With Sigma 1 Receptor Activity Improves Stroke Outcomes In Male Rats

Sigma-1 receptor ligands including agonists and antagonists have been shown to improve outcomes from experimental stroke when administered at delayed time points. However, clinical trials for one such agonist, cutamesine, failed to demonstrate benefit. In the present study, we sought to identify approved drugs that could be repurposed for Sigma-1 activity and the delayed treatment of stroke. High-throughput screening was used to identify Sigma-1 receptor selective binding and stimulation of brain-derived neurotrophic factor (BDNF) release for several potential ligands that are already approved for other indications. Two lead compounds, promethazine (an antihistamine) and oxeladin (a cough suppressant), were advance to in vivo studies. Both compounds displayed favorable oral absorption into the brain and high dose tolerance in rats. Neither compound significantly altered thrombosis in an in vitro blood coagulation assay. Daily oral administration of oxeladin (3 doses) or vehicle was started 48 hours after 90-minute transient middle cerebral artery occlusion in adult male Sprague-Dawley rats (n=12/group) and continued for 10 days in a treatment-blind manner. Rats receiving the two highest doses showed significant (P&lt;0.05, 2-way ANOVA and Dunnett’s test) improvements in Bederson scores (0.4±0.1 vs 1.5±0.2), an 11 point Neurological assessment (1.2±0.1 vs 3.9±0.2) , and the elevated body swing test (60% vs 90% bias) 1, 4, and 10 days after dosing compared to vehicle controls. A subset of rats was administered BrdU (50 mg/kg ip) every other day. However, there were no significant differences among groups in BrdU incorporation observed in the subventricular zone at 14 days after stroke. Additional studies are being performed to assess the mechanisms of neuroprotection. These data suggest that repurposing of approved/safe drugs with Sigma-1 receptor activity is a promising avenue for the treatment of chronic stroke.

Exploring Fatigue Effects on Performance Variation of Intensive Brain-Computer Interface (BCI) Practice

COVID-19 has been an emerging and rapidly evolving risk to people of the world in 2020. Facing this dangerous situation, many colleagues in Neurorestoratology did their best to avoid infection if themselves and their patients, and continued their work in the research areas described in the 2020 Yearbook of Neurorestoratology. Neurorestorative achievements and progress during 2020 includes recent findings on the pathogenesis of neurological diseases, neurorestorative mechanisms and clinical therapeutic achievements. Therapeutic progress during this year included advances in cell therapies, neurostimulation/neuromodulation, brain-computer interface (BCI), and pharmaceutical neurorestorative therapies, which improved neurological functions and quality of life for patients. Four clinical guidelines or standards of Neurorestoratology were published in 2020. Milestone examples include: 1) a multicenter randomized, double-blind, placebo-controlled study of olfactory ensheathing cell treatment of chronic stroke showed functional improvements; 2) patients after transhumeral amputation experienced increased sensory acuity and had improved effectiveness in work and other activities of daily life using a prosthesis; 3) a patient with amyotrophic lateral sclerosis used a steady-state visual evoked potential (SSVEP)-based BCI to achieve accurate and speedy computer input; 4) a patient with complete chronic spinal cord injury recovered both motor function and touch sensation with a BCI and restored ability to detect objects by touch and several sensorimotor functions. We hope these achievements motivate and encourage other scientists and physicians to increase neurorestorative research and its therapeutic applications.

A Study of Using Expected Effect to Improve the Covert Attention ERP-BCI

COVID-19 has been an emerging and rapidly evolving risk to people of the world in 2020. Facing this dangerous situation, many colleagues in Neurorestoratology did their best to avoid infection if themselves and their patients, and continued their work in the research areas described in the 2020 Yearbook of Neurorestoratology. Neurorestorative achievements and progress during 2020 includes recent findings on the pathogenesis of neurological diseases, neurorestorative mechanisms and clinical therapeutic achievements. Therapeutic progress during this year included advances in cell therapies, neurostimulation/neuromodulation, brain-computer interface (BCI), and pharmaceutical neurorestorative therapies, which improved neurological functions and quality of life for patients. Four clinical guidelines or standards of Neurorestoratology were published in 2020. Milestone examples include: 1) a multicenter randomized, double-blind, placebo-controlled study of olfactory ensheathing cell treatment of chronic stroke showed functional improvements; 2) patients after transhumeral amputation experienced increased sensory acuity and had improved effectiveness in work and other activities of daily life using a prosthesis; 3) a patient with amyotrophic lateral sclerosis used a steady-state visual evoked potential (SSVEP)-based BCI to achieve accurate and speedy computer input; 4) a patient with complete chronic spinal cord injury recovered both motor function and touch sensation with a BCI and restored ability to detect objects by touch and several sensorimotor functions. We hope these achievements motivate and encourage other scientists and physicians to increase neurorestorative research and its therapeutic applications.

Intravenous Bone Marrow Mononuclear Cells Transplantation Improves the Effect of Training in Chronic Stroke Mice

There is no effective treatment for chronic stroke if the acute or subacute phase is missed. Rehabilitation alone cannot easily achieve a dramatic recovery in function. In contrast to significant therapeutic effects of bone marrow mononuclear cells (BM-MNC) transplantation for acute stroke, mild and non-significant effects have been shown for chronic stroke. In this study, we have evaluated the effect of a combination of BM-MNC transplantation and neurological function training in chronic stroke. The effect of BM-MNC on neurological functional was tested four weeks after permanent middle cerebral artery occlusion (MCAO) insult in mice. BM-MNC (1 × 105cells in 100 μl PBS) were injected into the vein of MCAO model mice, followed by behavioral tests as functional evaluations. Interestingly, there was a significant therapeutic effect of BM-MNC only when repeated training was performed. This suggested that cell therapy alone was not sufficient for chronic stroke treatment; however, training with cell therapy was effective. The combination of these differently targeted therapies provided a significant benefit in the chronic stroke mouse model. Therefore, targeted cell therapy via BM-MNC transplantation with appropriate training presents a promising novel therapeutic option for patients in the chronic stroke period.

Axonal remodeling of the corticospinal tract during neurological recovery after stroke.

Stroke remains the leading cause of long-term disability. Hemiparesis is one of the most common post-stroke motor deficits and is largely attributed to loss or disruption of the motor signals from the affected motor cortex. As the only direct descending motor pathway, the corticospinal tract (CST) is the primary pathway to innervate spinal motor neurons, and thus, forms the neuroanatomical basis to control the peripheral muscles for voluntary movements. Here, we review evidence from both experimental animals and stroke patients, regarding CST axonal damage, functional contribution of CST axonal integrity and remodeling to neurological recovery, and therapeutic approaches aimed to enhance CST axonal remodeling after stroke. The new insights gleaned from preclinical and clinical studies may encourage the development of more rational therapeutics with a strategy targeted to promote axonal rewiring for corticospinal innervation, which will significantly impact the current clinical needs of subacute and chronic stroke treatment.

The use of ADSCs as a treatment for chronic stroke.

Stroke is one of the disorders for which clinically effective therapeutic modalities are most needed, and numerous ways have been explored to attempt to investigate their feasibilities. However, ischemic- or hemorrhagic-induced inflammatory neuron death causes irreversible injuries and infarction regions, and there are currently no truly effective drugs available as therapy. It is therefore urgent to be able to provide a fundamental treatment method to regenerate neuronal brain cells, and therefore, the use of stem cells for curing chronic stroke could be a major breakthrough development. In this review, we describe the features and classification of stroke and focus on the benefits of adipose tissue-derived stem cells and their applications in stroke animal models. The results show that cell-based therapies have resulted in significant improvements in neuronal behaviors and functions through different molecular mechanisms, and no safety problems have so far arisen after transplantation. Further, we propose a clinical possibility to create a homing niche by reducing the degree of invasive intracerebroventricular transplantation and combining it with continuous intravenous administration to achieve a complete cure.

Comparison of the neuropoietic activity of gene-modified versus parental mesenchymal stromal cells and the identification of soluble and extracellular matrix-related neuropoietic mediators

IntroductionTransplanting mesenchymal stromal cells (MSCs) or their derivatives into a neurodegenerative environment is believed to be beneficial because of the trophic support, migratory guidance, immunosuppression, and neurogenic stimuli they provide. SB623, a cell therapy for the treatment of chronic stroke, currently in a clinical trial, is derived from bone marrow MSCs by using transient transfection with a vector encoding the human Notch1 intracellular domain. This creates a new phenotype, which is effective in experimental stroke, exhibits immunosuppressive and angiogenic activity equal or superior to parental MSCs in vitro, and produces extracellular matrix (ECM) that is exceptionally supportive for neural cell growth. The neuropoietic activity of SB623 and parental MSCs has not been compared, and the SB623-derived neuropoietic mediators have not been identified.MethodsSB623 or parental MSCs were cocultured with rat embryonic brain cortex cells on cell-derived ECM in a previously characterized quantitative neuropoiesis assay. Changes in expression of rat neural differentiation markers were quantified by using rat-specific qRT-PCR. Human mediators were identified by using expression profiling, an enzymatic crosslinking activity, and functional interference studies by means of blocking antibodies, biologic inhibitors, and siRNA. Cocultures were immunolabeled for presynaptic vesicular transporters to assess neuronal specialization.ResultsAmong six MSC/SB623 pairs, SB623 induced expression of rat neural precursor, oligodendrocyte, and astrocyte markers on average 2.6 to 3 times stronger than did their parental MSCs. SB623 expressed significantly higher FGF2, FGF1, and BMP4, and lower FGFR1 and FGFR2 levels; and human FGF1, FGF2, BMPs, and HGF were implicated as neuropoietic mediators. Neural precursors grew faster on SB623- than on MSC-derived ECM. SB623 exhibited higher expression levels and crosslinking activity of tissue transglutaminase (TGM2). TGM2 silencing reduced neural precursor growth on SB623-ECM. SB623 also promoted the induction of GABA-ergic, but not glutamatergic, neurons more effectively than did MSCs.ConclusionsThese data demonstrate that SB623 cells tend to support neural cell growth more effectively than their parental MSCs and identify both soluble and insoluble mediators responsible, at least in part, for enhanced neuropoietic potency of SB623. The neuropoiesis assay is a useful tool for identifying beneficial factors produced by MSCs and their derivatives.

Comparing the angiogenic potency of naïve marrow stromal cells and Notch-transfected marrow stromal cells

BackgroundAngiogenesis is a critical part of the endogenous repair process in brain injury and disease, and requires at least two sequential steps. First, angiogenic sprouting of endothelial cells occurs, which entails the initial proliferation of endothelial cells and remodeling of the surrounding extracellular matrix. Second, vessel stabilization is necessary to prevent vascular regression, which relies on vascular smooth muscle recruitment to surround the young vessels. Marrow stromal cells (MSCs) have been shown to promote revascularization after hindlimb ischemia, cardiac ischemia, and stroke. SB623 cells are derived from marrow stromal cells by transfection with a Notch1 intracellular domain (NICD)-expressing plasmid and are known to elicit functional improvement in experimental stroke. These cells are currently used in human clinical testing for treatment of chronic stroke. In the current study, the angiogenic property of SB623 cells was investigated using cell-based assays.MethodsAngiogenic paracrine factors secreted by SB623 cells and the parental MSCs were identified using the Qantibody Human Angiogenesis Array. To measure the angiogenic activity of conditioned medium from SB623 cells and MSCs, endothelial tube formation in the human umbilical vein endothelial cell (HUVEC) assay and endothelial cell sprouting and branching in the rodent aortic ring assay were quantified. To validate the angiogenic contribution of VEGF in conditioned medium, endothelial cells and aortic rings were treated with SU5416, which inhibits VEGFR2 at low dose.ResultsConditioned medium from SB623 cells promoted survival and proliferation of endothelial cells under serum-deprived conditions and supports HUVEC vascular tube formation. In a rodent aortic ring assay, there was enhanced endothelial sprouting and branching in response to SB623-derived conditioned medium. SU5416 treatment partially reversed the effect of conditioned medium on endothelial cell survival and proliferation while completely abrogate HUVEC tube formation and endothelial cell sprouting and branching in aortic ring assays.ConclusionsThese data indicate that SB623 cell-secreted angiogenic factors promoted several aspects of angiogenesis, which likely contribute to promoting recovery in the injured brain.

The combination of stem cell factor and granulocyte-colony stimulating factor for chronic stroke treatment in aged animals

BackgroundStroke occurs more frequently in the elderly population and presents the number one leading cause of persistent disability worldwide. Lack of effective treatment to enhance brain repair and improve functional restoration in chronic stroke, the recovery phase of stroke, is a challenging medical problem to be solved in stroke research. Our early study has revealed the therapeutic effects of stem cell factor (SCF) in combination with granulocyte-colony stimulating factor (G-CSF) (SCF+G-CSF) on chronic stroke in young animals. However, whether this treatment is effective and safe to the aged population remains to be determined.MethodsCortical brain ischemia was produced in aged C57BL mice or aged spontaneously hypertensive rats. SCF+G-CSF or equal volume of vehicle solution was subcutaneously injected for 7 days beginning at 3–4 months after induction of cortical brain ischemia. Using the approaches of biochemistry assays, flow cytometry, pathology, and evaluation of functional outcome, several doses of SCF+G-CSF have been examined for their safety and efficiency on chronic stroke in aged animals.ResultsAll tested doses did not show acute or chronic toxicity in the aged animals. Additionally, SCF+G-CSF treatment in chronic stroke of aged animals mobilized bone marrow stem cells and improved functional outcome in a dose-dependent manner.ConclusionsSCF+G-CSF treatment is a safe and effective approach to chronic stroke in the aged condition. This study provides important information needed for developing a new therapeutic strategy to improve the health of older adults with chronic stroke.

The Combined Impact of Virtual Reality Neurorehabilitation and Its Interfaces on Upper Extremity Functional Recovery in Patients With Chronic Stroke

Although there is strong evidence on the beneficial effects of virtual reality (VR)-based rehabilitation, it is not yet well understood how the different aspects of these systems affect recovery. Consequently, we do not exactly know what features of VR neurorehabilitation systems are decisive in conveying their beneficial effects. To specifically address this issue, we developed 3 different configurations of the same VR-based rehabilitation system, the Rehabilitation Gaming System, using 3 different interface technologies: vision-based tracking, haptics, and a passive exoskeleton. Forty-four patients with chronic stroke were randomly allocated to one of the configurations and used the system for 35 minutes a day for 5 days a week during 4 weeks. Our results revealed significant within-subject improvements at most of the standard clinical evaluation scales for all groups. Specifically we observe that the beneficial effects of VR-based training are modulated by the use/nonuse of compensatory movement strategies and the specific sensorimotor contingencies presented to the user, that is, visual feedback versus combined visual haptic feedback. Our findings suggest that the beneficial effects of VR-based neurorehabilitation systems such as the Rehabilitation Gaming System for the treatment of chronic stroke depend on the specific interface systems used. These results have strong implications for the design of future VR rehabilitation strategies that aim at maximizing functional outcomes and their retention. Clinical Trial Registration- This trial was not registered because it is a small clinical study that evaluates the feasibility of prototype devices.

Entrenamiento aeróbico y de fuerza en la rehabilitación del ictus

Objectives To review the literature and explain the effects and benefits of aerobic and strength training in subacute and chronic stroke. Search strategy A bibliographic review of the last 10 years was conducted using the databases: PubMed, PEDro, Biblioteca Cochrane Plus, Enfispo and Cuiden. Study selection Meta-analysis, systematic reviews and controlled and randomized trials were selected. Summary of results Physical exercise improves muscular strength and endurance, gait speed and endurance and cardiorespiratory capacity. It can also develop functional skills, speed of information processing, motor learning, implicit memory and symptoms of depression. Conclusions Aerobic and strength trainings are a fundamental part of subacute and chronic stroke treatment, because they improve functionality, gait capacity and neurological sequels.

Semaphorin 6A Improves Functional Recovery in Conjunction with Motor Training after Cerebral Ischemia

BackgroundWe have previously identified Semaphorin 6a (Sema6A) as an upregulated gene product in a gene expression screen in cortical ischemia [1]. Semaphorin 6a was regulated during the recovery phase following ischemia in the cortex. Semaphorin 6a is a member of the superfamily of semaphorins involved in axon guidance and other functions. We hypothesized that the upregulation indicates a crucial role of this molecule in post-stroke rewiring of the brain. Here we have tested this hypothesis by overexpressing semaphorin 6a in the cortex by microinjection of a modified AAV2-virus. A circumscribed cortical infarct was induced, and the recovery of rats monitored for up to 4 weeks using a well-established test battery (accelerated rotarod training paradigm, cylinder test, adhesive tape removal). We observed a significant improvement in post-ischemic recovery of animals injected with the semaphorin 6a virus versus animals treated with a control virus. We conclude that semaphorin 6a overexpressed in the cortex enhances recovery after cerebral ischemia. Semaphorin 6a may represent a novel therapeutic candidate for the treatment of chronic stroke.

Randomized Clinical Stroke Trials in 2009

Problem statement: Stroke ranks as the leading cause of serious, long-term disability and death world-wide. It is estimated direct and indirect cost of stroke for 2009 was $68.9 billion. Approach: The objective of this review was to examine the effectiveness of emerging pharmacotherapy’s in patients with acute (≤2 weeks), sub-acute (2-12 weeks) and chronic (≥12 weeks) stroke studied in Randomized Control Trials (RCT’s) published in 2009. Medline search was performed to identify all RCT’s in acute, sub-acute and chronic stroke treatment in the year 2008. The search strategy used for Pub Med included key words such as Randomized Controlled Trials (RCT), Stroke OR cerebrovascular disorders OR CVA, Ischemic stroke OR ischemia, Hemorrhage OR intraparenchymal hemorrhage OR subarachnoid hemorrhage, Thrombolytics OR tissue plasminogen activator OR alteplase OR t-PA, Diabetes mellitus OR hyperglycemia, Hypertension OR raised blood pressure, Aspirin OR anti-platelets, Warfare OR anticoagulant, Antidepressants , Neuroprotectants and Coiling OR stents OR endovascular. Search limits included Human, Adult (age>19 years), English language and Publication date: 1/1/2009-12/31/2009. Results: Eleven categories of 27 RCT’s were found and analyzed. Conclusion: There was sufficient evidence to suggest that: (1) extending the time-window for administration of desmoteplase between 3-9 h after ischemic stroke onset did not improve clinical outcome; (2) at present neither lidocaine, erythropoietin or ropinotan had been effective neuroprotective agents in ischemic stroke; (3) treatment with dabigatran was associated with lower rate of stroke and systemic embolism in patients with non-valvular aerial fibrillation; (4) memantine and constraint-induced aphasia therapy were able to reduce the severity of aphasia in chronic post-stroke aphasia and (5) percutaneous closure of the left aerial appendage can be an effective alternative to chronic warfare treatment.

Randomized Clinical Stroke Trials In 2008

Problem statement: Stroke ranks as the third leading cause of death and the leading cause of serious, long-term disability; estimated direct and indirect cost of stroke for 2009 was $68.9 billion. Approach: The objective of this review was to examine the effectiveness of emerging pharmacotherapies in patients with acute (≤2 weeks), sub-acute (2-12 weeks) and chronic (≥12 weeks) stroke studied in Randomized Control Trials (RCT's) published in 2008. Medline search was performed to identify all RCT’s in acute, sub-acute and chronic stroke treatment in the year 2008. The search strategy used for PubMed included key words such as Randomized Controlled Trials (RCT), Stroke OR cerebrovascular disorders OR CVA, Ischemic stroke OR ischemia, Hemorrhage OR intraparenchymal hemorrhage OR subarachnoid hemorrhage, Thrombolytics OR tissue plasminogen activator OR alteplase OR t-PA, Diabetes mellitus OR hyperglycaemia, Hypertension OR raised blood pressure, Aspirin OR anti-platelets, Warfarin OR anticoagulant, Antidepressants, Neuroprotectants and Coiling OR stents OR endovascular. Search limits included Human, Adult (age >19 years), English language and Publication date: 1/1/2008 to 12/31/2008. Results: Eleven categories of 21 RCT’s were found and analyzed. Conclusion/Recommendations: There is sufficient evidence to suggest that: (1) extending the time-window for administration of alteplase from 3-4.5 h after stroke onset does improve clinical outcome; (2) treatment of hypertension in the elderly does reduce rate of stroke, cardiac failure and death from stroke and (3) at present there are no neuroprotectants on the horizon.

Schlaganfall

Ischemic stroke is a very frequent neurological disorder. It's incidence is increasing as western societies are aging. Effective therapies that reduce mortality and increase the chances of living symptom-free or, at least, in independence are available. Intravenous or intraarterial thrombolysis is an effective treatment with a number needed to treat of 6 if given within 4.5 hours after symptom onset. The safe use of thrombolysis requires an effective and repeatedly trained workflow established within a team of a neurologist and specialized nursing staff in an optimized environment (admission, imaging facility, laboratory, stroke unit). After peracute treatment, the patient should be transferred to a stroke unit. This unit is a spatially defined intermediate care unit with specifically trained personnel (physicians, nurses, therapists). Treating the patient in a stroke unit is as effective in improving outcome as thrombolysis and also reduces the length of hospital stay. In contrast to thrombolysis, which can be provided, on average, to only 5% of stroke patients, stroke unit care is applicable to most. The organization of medical care in most European countries and in Switzerland separate the acute phase from subacute rehabilitation and chronic stroke treatment. This can be highly confusing for the patient who, during the course of the disease, meets different physicians, nurses and therapists with often diverging opinions about prognosis and therapies. Consistent treatment approaches and patient/caregiver information is necessary and can only be implemented by providing a homogeneous pathway for continuous stroke care.