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| POST STROKE RESTORATIVE THERAPIES: DRUGS, DEVICES AND ROBOTICS |
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| Year : 2018 | Volume
: 5
| Issue : 1 | Page : 39-42 |
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Post stroke restorative therapies: Drugs, devices and robotics
MV Padma Srivastava, Ashu Bhasin
Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
| Date of Web Publication | 28-Jan-2019 |
Correspondence Address:
M V Padma Srivastava
Department of Neurology, All India Institute of Medical Sciences, New Delhi
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/astrocyte.astrocyte_50_18
Restorative therapies in neurology aim to improve outcome and function by promoting plasticity within a therapeutic time window between days to weeks to years. In this article, the mechanisms by which cell-based, pharmacological and robotic treatments stimulate endogenous brain remodeling after stroke, particularly neurogenesis, axonal plasticity, and white-matter integrity, are described with a brief outline of the potential of neuroimaging (functional magnetic resonance imaging) techniques. Stem cells aid stroke recovery through mechanisms depending on the type of cells used. Transplanted embryonic stem cells, induced pluripotent cells, and neural stem cells can replace the missing brain cells in the infarcted area, whereas adult stem cells, such as multipotent stromal cells and mononuclear cells, provide trophic support to enhance self-repair systems such as endogenous neurogenesis. Noninvasive brain stimulation provides a valuable tool for interventional neurophysiology by modulating brain activity in a specific distributed, corticosubcortical network. Elucidating the underlying mechanisms of cell-based, pharmacological and rehabilitative therapies is of primary interest and crucial for translation of treatments to clinical use. This will provide an impetus for the development of superior, advanced, and cost-effective neurorestorative interventions that will enhance stroke recovery. Keywords: Devices, drugs, neural plasticity, stroke recovery
How to cite this article:
Padma Srivastava M V, Bhasin A. Post stroke restorative therapies: Drugs, devices and robotics. Astrocyte 2018;5:39-42 |
| Introduction | |  |
Restorative therapies aim to improve outcome and function by promoting plasticity within a therapeutic time window between days to weeks to years. The armamentarium includes growth factors, cell-based therapies, drugs, and devices. Pharmacological treatment includes drugs that increase cyclic guanosine monophosphate (cGMP; e.g. phosphodiesterase 5 inhibitors, such as sildenafil and tadalafil), statins, erythropoietin, granulocyte-colony stimulating factor, and minocycline.[1],[2],[3],[4]
Cell-based interventions: Stem cells
Stem cells can be defined as clonogenic cells that have the capacity to self-renew and differentiate into multiple cell lineages. They are divided according to the body's development process and their ability to form other cells.[5],[6],[7],[8],[9],[10] Their presumed participation in repair and regeneration raised high expectations to cure diseases that have thus far proven resistant to conventional therapy such as stroke.
Human umbilical cord blood cells
These cells are derived from umbilical cord blood with a potential of differentiation into neural lineages. When exposed to nerve growth factor and retinoic acid, the derived umbilical cord blood cells produce progeny that shows positivity for neural and glial cells' markers.[11]
Immortalized cell lines
These cell lines are derived by infecting neuroepithelial precursor cells from predefined central nervous system (CNS) regions before terminal mitosis, with a retrovirus encoding an immortalizing oncogene.[12]
Fetal neural stem cells
These cells maintain a normal karyotype for a significant number of passages in culture and can produce a large number of neurons and astrocytes and are harvested from the postmortem human fetal brain.[13]
Adult neural stem cells
Neural stem cells are defined as undifferentiated cells that are able to self-renew and generate three major cell types of CNS: neurons, astrocytes, and oligodendrocytes, signifying their pluripotent nature.[5],[6],[13]
Bone marrow–derived cells
These have hematopoietic and nonhematopoietic components, the former being abundant in bone marrow.[14] Mobilized peripheral blood is also a clinical source of heme cells, containing a mixture of hematopoietic stem and progenitor cells enriched with CD34.[15] These cells have the potential to regenerate the brain tissue by release of neurotrophic growth hormones. The other component of bone marrow contains mesenchymal stem cells or multipotent stromal cells described as colony-forming units that adhere to cell culture surfaces and can be differentiated into osteoblasts, adipocytes, and chondrocytes.[16],[17],[18]
Induced pluripotent cells
These cells are similar to human embryonic stem cells in morphology, proliferation, surface antigens, gene expression, epigenetic status of pluripotent cell-specific genes, and telomerase activity.[19]
| Clinical Trials of Stem Cell Research in Stroke | | |
Among all types of cells, bone marrow–derived stem cells are used frequently in clinical trials with stroke. Multiple studies from AIIMS, New Delhi, report successful transplanted bone marrow–derived mononuclear and mesenchymal stem cells in chronic stroke.[20],[21],[22] The functional benefits after neural transplantation are likely to be mediated by one of a host of hypothesized mechanisms.[23],[24]
Another observational controlled study evaluated the feasibility and efficacy of autologous mononuclear stem cells' infusion intravenously in patients with chronic ischemic stroke using clinical scores and functional imaging (functional magnetic resonance imaging and diffusion tensor imaging). Of 24 patients recruited, 12 received a mean of 54.6 million Mononuclear stem cells (MNC) cells. On follow-up of 24 weeks, only modified Barthel index (mBI) showed statistically significant improvement (P < 0.05) in the stem cells' arm. There was an increased number of cluster activation of Brodmann areas BA4 and 6, after stem-cell infusion. Similar results were observed in a parallel study using culture expanded autologous mesenchymal stem cells.[20],[21],[25]
| Role of Noninvasive Brain Stimulation | | |
Noninvasive brain stimulation (NIBS) provides a valuable tool for interventional neurophysiology by modulating brain activity in a specific distributed, corticosubcortical network.[26],[27],[28],[29],[30],[31] The two most commonly used techniques for NIBS are transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). TMS is a neurostimulation and neuromodulation application, whereas tDCS is a purely neuromodulatory intervention.[32],[33],[34],[35]
Hsu et al. conducted a meta-analysis on 18 studies involving 392 patients on efficacy of TMS after stroke. A significant effect size of 0.55 was found for motor outcome [95% confidence interval (CI), 0.37–0.72) with subgroup analyses demonstrating more prominent effects on subcortical stroke (mean effect size ~0.73; 95% CI, 0.44–1.02).[30] Recent data suggest that intermittent theta-burst stimulation over the affected hemisphere might be a useful intervention.[36],[37]
In tDCS, although the currents applied do not usually elicit action potentials, they modify the transmembrane neuronal potential and thus influence the level of excitability modulating the firing rate of individual neurons.[38],[39]
| Role of Mirror Therapy/virtual Reality | | |
A pilot study confirmed the positive effects of mirror therapy on facilitation in upper limb hemiparesis after stroke.[40] In a systematic review, 14 studies were included with 9–121 participants. It was found that mirror therapy had a significant effect on motor function (Standard mean deviation (SMD) 0.61; 95% CI, ~0.22 to1; P = 0.002; I2 = 75%).[41] A study from AIIMS, New Delhi, used mirror therapy in chronic stroke patients with the help of a web cam that captured the normal hand which was seen as affected on the laptop screen. Bilateral hand training was administered to patients and it was observed that Mirror therapy (MT) improved hand function in FM and mBI scores along with an increased in laterality index in ipsilesional BA 4 and 6.[42]
| Role of Cimt and Electrical Stimulation | | |
Constraint-induced movement therapy (CIMT) has been investigated in 51 randomized controlled trials (RCTs) including 1784 patients with adult stroke; only 15 trials included patients within the first 3 months after stroke. From systematic review,[43],[44],[45] it is evident that original and modified versions of CIMT have a robust, clinically meaningful impact on patient's outcomes for arm-hand activities, self-reported hand use in daily life, and basic activities of daily living, making it one of the most effective interventions for the paretic limb after stroke. Neuromuscular electrical stimulation and functional electrical stimulation induce depolarization of peripheral neurons and subsequently elicit muscle contractions.[46],[47]
| Robotic Technology in Stroke | | |
The introduction of robotic systems into clinical practice is useful in promoting a cost-effective use of human resources and standardization of rehabilitation treatments.[48],[49],[50],[51],[52]
| Pharmacological Agents | | |
Nitric oxide
Nitric oxide (NO) is an “endothelial-derived relaxing factor” which is involved in maintaining endothelial cell integrity, and participating in hemodynamic homeostasis.[53] The increased expression of neuronal NO synthase within the subvenricular zone during embryogenesis suggests an important role for the NO pathway in neurogenesis, increasing cGMP levels, and aid in recovery.[54]
GABA: Gamma amino butyric acid
GABA may help in recovery after stroke involving remapping of the neuronal circuitry in the regions adjacent to the site of injury or the peri-infarct zone.[55],[56]
Selective serotonin reuptake inhibitors
Animal studies suggest that selective serotonin reuptake inhibitors (SSRIs) may be involved in neurogenesis and activation of cortical motor areas modulating neuronal plasticity.[57] A meta-analysis of RCTs onstroke patients treated with SSRI compared with usual care or sham found that these drugs are associated with an improvement in functionality, neurological impairment, disability, and depression.[58],[59],[60]
Minocycline
Studies have shown that minocycline has notable beneficial effects in animal models of global and transient focal cerebral ischemia.[61],[62] In a randomized single-blinded study, we studied the effects of oral minocycline (200 mg/day for 5 days) after stroke versus placebo. Of 50 patients included in the trial, patients who received minocycline had better recovery in stroke outcome as noted on National institute of health stroke scale (NIHSS), mBI and modified rankin score (mRS).[63]
| Conclusion | | |
Neurorestoration is a concept that has been proven emphatically in several experimental models and clinical studies of stroke. Elucidating the underlying mechanisms of cell-based, pharmacological and rehabilitative therapies is crucial for translation of treatments to clinical use. The knowledge must provide an impetus for the development of superior, advanced, and cost-effective neurorestorative interventions that will enhance stroke recovery.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Zhang ZG, Chopp M. Neurorestorative therapies for stroke: Underlying mechanisms and translation to the clinic. Lancet Neurol 2009;8:491-500.  |
| 2. | Burke E, Cramer SC. Biomarkers and predictors of restorative therapy effects after stroke. Curr Neurol Neurosci Rep 2013;13:329. |
| 3. | Cramer SC. Repairing the human brain after stroke. II Restorative therapies. Ann Neurol 2008;63:549-60. |
| 4. | Nudo RJ. Recovery after brain injury. Mechanisms and principles. Front Hum Neurosci 2013;7:1-9. |
| 5. | Young HE, Black AC Jr. Adult stem cells. Anat Rec A Discov Mol Cell Evol Biol 2004;276:75-102. |
| 6. | Jaenisch R, Young R. Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell 2008;132:567-82. |
| 7. | Tandon PN. Brain cells – Recently unveiled secrets: Their clinical significance. Neurol India 2007;55:322-7. [ PUBMED] [Full text] |
| 8. | Takahashi K, Okita K, Nakagawa M, Yamanaka S. Induction of pluripotent stem cells from fibroblast cultures. Nat Protoc 2007;2:3081-9. |
| 9. | Yamanaka S. Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell 2007;1:39-49. |
| 10. | Hess DC, Borlongan CV. Stem cells and neurological diseases. Cell Prolif 2008(Suppl 1):94-114. |
| 11. | Yu G, Borlongan CV, Stahl CE, Hess DC, Ou Y, Kaneko Y, et al. Systemic delivery of umbilical cord blood cells for stroke therapy: A review. Restor Neurol Neurosci 2009;27:41-54. |
| 12. | Patkar S, Tate R, Modo M, Plevin R, Carswell HV. Conditionally immortalised neural stem cells promote functional recovery and brain plasticity after transient focal cerebral ischemia in mice. Stem Cell Res 2012;8:14-25. |
| 13. | Tabar V, Panagiotakos G, Greenberg ED, Chan BK, Sadelain M, Gutin PH, et al. Migration and differentiation of neural precursors derived from human embryonic stem cells in the rat brain. Nat Biotechnol 2005;23:601-6. |
| 14. | Morrison SJ, Uchida N, Weissman IL. The biology of hematopoietic stem cells. Ann Rev Cell Dev Biol1995;11:35-71. |
| 15. | Domen J, Weissman IL. Self-renewal, differentiation or death: Regulation and manipulation of hematopoietic stem cell fate. Mol Med Today 1999;5:201-8. |
| 16. | Bianco P, Riminucci M, Gronthos S, Robey PG. Bone marrow stromal stem cells: Nature, biology, and potential applications. Stem Cells 2001;19:180-92. |
| 17. | Kolf CM, Cho E, Tuan RS. Mesenchymal stromal cells. Biology of adult mesenchymal stem cells: Regulation of niche, self-renewal and differentiation. Arthritis Res Ther 2007;9:204. |
| 18. | Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez, XR et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002;418:41-9. |
| 19. | Yu F, Li Y, Morshead CM. Induced pluripotent stem cells for the treatment of stroke: The potential and the pitfalls. Current Stem Cell Res Ther 2013;8:407-14. |
| 20. | Bhasin A, Srivastava MV, Mohanty S, Bhatia R, Kumaran SS. Stem cell therapy: A clinical trial of stroke. Clin Neurol Neurosurg 2013;115:1003-8. |
| 21. | Bhasin A, Srivastava MVP, Bhatia R, Mohanty S, Kumaran SS, Bose S. Autologous Intravenous mononuclear stem cell therapy in chronic ischemic stroke. J Stem Cells Regen Med 2012;8:181-9. |
| 22. | Bhasin A, Srivastava MV, Kumaran SS, Mohanty S, Bhatia R, Bose S, et al. Autologous mesenchymal stem cells in chronic stroke. Cerebrovasc Dis Extra 2011;1:93-104. |
| 23. | Meamar R, Dehghani L, Ghasemi L, Khorvash F, Shaygannejad V. Stem cell therapy in stroke: A review literature. Int J Prev Med 2013;4:S139. |
| 24. | Bang YO. Clinical trials of adult stem cell therapy in patients with ischemic stroke. J Clin Neurol 2016;12:14-20. |
| 25. | Bhasin A, Srivastava MV, Mohanty S, Vivekanandhan S, Sharma S, Kumaran S, et al. Paracrine mechanisms of intravenous bone marrow-derived mononuclear stem cells in chronic ischemic stroke. Cerebrovasc Dis Extra 2016;6:107-19. |
| 26. | Auriat AM, Neva JL, Peters S, Ferris JK, Boyd LA. A review of transcranial magnetic stimulation and multimodal neuroimaging to characterize post-stroke neuroplasticity. Front Neurol 2015;6:226-31. |
| 27. | Hoyer EH, Celhik PA. Understanding and enhancing motor recovery after stroke using transcranial magnetic stimulation. Restor Neurol Neurosc 2011;29:395-409. |
| 28. | Reato D, Rahman A, Bikson M, Parra LC. Low-intensity electrical stimulation affects network dynamics by modulating population rate and spike timing. J Neurosci 2010;45:15067-79. |
| 29. | Corti M, Pattern C, Triggs W. Repetitive transcranial magnetic stimulation of motor cortex after stroke. Arch Phys Med Rehabil 2012;91:254-70. |
| 30. | Hsu WY, Cheng CH, Liao KK, Lee IH., Lin YY. Effects of repetitive transcranial magnetic stimulation on motor functions in patients with stroke: A meta-analysis. Stroke 2012;43, 1849-85. |
| 31. | Kubis N. Non-invasive brain stimulation to enhance post-stroke recovery. Front Neural Circuits 2016;10:56-62. |
| 32. | Cicinelli P, Pasqualetti P, Zaccagnini M. Imagery induced cortical excitability in Stroke: A transcranial magnetic stimulation study. Cerebral Cortex 2006;16:247-53. |
| 33. | Plautz EJ, Barbay S, Frost SB, Friel KM, Dancause N, Zoubina EV, et al. Post-infarct cortical plasticity and behavioral recovery using concurrent cortical stimulation and rehabilitative training: A feasibility study in primates. Neurol Res 2003;25:801-10. |
| 34. | Kleim JA, Kleim ED, Cramer SC. Systematic assessment of training-induced changes in corticospinal output to hand using frameless stereotaxic transcranial magnetic stimulation. Nat Protoc 2007;2:1675-84. |
| 35. | Gomez A, Schjetnan P, Faraji J, Gerlinde A, Tatsuno MM, Luczak A. Transcranial direct current stimulation in stroke rehabilitation: A review of recent advancements. Review. Stroke Res Treat 2013;2013:170456. |
| 36. | Leindenberg R, Rengha V, Zhu LL, Nair D, Schlaug G. Bihemispheric brain stimulation facilitates motor recovery in chronic stroke patients. Neurology 2010;75:2176-84. |
| 37. | Kim DY, Ohn SH, Yang EJ, Park CI, Jung KJ. Enhancing motor performance by anodal transcranial direct current stimulation in subacute stroke patients. Am J Phys Med Rehabilit 2009;88:829-36. |
| 38. | Fregni S, Boggio PS, Mansur CG, Wagner T, Ferreira MJ, Lima MC, et al. Transcranial direct current stimulation of the unaffected hemisphere in stroke patients. Neuroreport 2005;16:1551-5. |
| 39. | Webster BR, Celnik PA, Cohen LG. Noninvasive brain stimulation in stroke rehabilitation. NeuroRx 2006;3:474-81. |
| 40. | Ramachandran VS, Altschuler EL, Stone L, Al-Aboudi M, Schwartz E, Siva N. Can mirrors alleviate visual hemineglect? Med Hypotheses 1999;52:303-5. |
| 41. | Dohle C, Pullen J, Nakaten A, Kust J, Rietz C, Karbe H. Mirror therapy promotes recovery from severe hemiparesis: A randomized controlled trial. Neurorehabil Neural Repair 2009;23:209-17. |
| 42. | Bhasin A, Srivastava MV, Kumaran SS, Bhatia R, Mohanty S. Neural interface of mirror therapy in chronic stroke. A functional magnetic resonance imaging study. Neurol India 2012;60:570-6. [ PUBMED] [Full text] |
| 43. | Kwakkel G, Veerbeek JM, Wegen EEM, Wolf SL. Constraint-induced movement therapy after stroke. Lancet Neurol 2015;14:224-34. |
| 44. | Reiss A, Wolf S, Hammel E, McLeod E, Williams E. Constraint-induced movement therapy (CIMT): Current perspectives and future directions. Stroke Res Treat 2012;8:159391-6. |
| 45. | Nijland R, Kwakkel G, Bakers J, van Wegen E. Constraint-induced movement therapy for the upper paretic limb in acute or sub-acute stroke: A systematic review. Int J Stroke 2011;6:425-33. |
| 46. | Sheffler LR, Chae J. Neuromuscular electrical stimulation in neurorehabilitation. Muscle Nerve 2007;35:562-90. |
| 47. | Quandt F, HummeL FC. The influence of functional electrical stimulation on hand motor recovery in stroke patients: A review. Exp Transl Stroke Med 2014;6:9-15. |
| 48. | Masiero S, Celia A, Rosati G, Armani M. Robotic-assisted rehabilitation of the upper limb after acute stroke. Arch Phys Med Rehabil 2007;88:142-7. |
| 49. | Masiero S, Celia A, Armani M, Rosati G. A novel robot device in rehabilitation of post-stroke hemiplegic upper limbs. Aging Clin Exp Res 2006;18:531-5. |
| 50. | Hornby TG, Campbell DD, Kahn JH, Demott T, Moore JL, Roth HR. Enhanced gait-related improvements after therapist-versus robotic-assisted locomotor training in subjects with chronic stroke: A randomized controlled study. Stroke 2008;39:1786-92. |
| 51. | Mayr A, Kofler M, Quirbach E, Matzak H, Fröhlich K, Saltuari L. Prospective, blinded, randomized crossover study of gait rehabilitation in stroke patients using the Lokomat gait orthosis. Neurorehabil Neural Repair 2007;21:307-14. |
| 52. | Lo AC, Guarino PD, Richards LG, Haselkorn JK, Wittenberg GF, Federman DG, et al. Robot-assisted therapy for long-term upper-limb impairment after stroke. N Engl J Med; 362:1772-83. |
| 53. | Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327:524-6. |
| 54. | Bredt DS, Snyder SH. Nitric oxide: A physiologic messenger molecule. Ann Rev Biochem 1994;63:175-95. |
| 55. | Zhang RL, Zhang Z, Zhang L, Wang Y, Zhang C, Choop M. Delayed treatment with sildenafil enhances neurogenesis and improves functional recovery in aged rats after focal cerebral ischemia. J Neurosci Res. 2006;83:1213-1219 |
| 56. | Berends HI, Nijlant JM, Movig KL, Van Putten MJ, Jannink MJ, Ijzerman MJ. The clinical use of drugs influencing neurotransmitters in the brain to promote motor recovery after stroke: A Cochrane systematic review. Eur J Phys Rehabil Med 2009;45:621-30. |
| 57. | Acler M, Robol E, Fiaschi A, Manganotti P. A double blind placebo RCT to investigate the effects of serotonergic modulation on brain excitability and motor recovery in stroke patients. J Neurol 2009;256:1152-8. |
| 58. | Pariente J, Loubinoux I, Carel C, Albucher JF, Leger A, Manelfe C, et al. Fluoxetine modulates motor performance and cerebral activation of patients recovering from stroke. Ann Neurol 2001;50:718-29. |
| 59. | Chollet F, Tardy J, Albucher JF, Thalamas C, Berard E, Lamy C, et al. Flouxetine for motor recovery after acute ischemic stroke (FLAME): A randomized, placebo-controlled trial. Lancet Neurol 2001;10:123-30. |
| 60. | Mead GE, Hsieh CF, Lee R, Kutlubaev MA, Claxton A, Hankey GJ, et al. Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery. Cochrane Database Syst Rev 2010;310:1066-7. |
| 61. | Fagan SC, Waller JL, Nichols FT, Edwards DJ, Pettigrew LC, Clark WM, et al. Minocycline to improve neurologic outcome in stroke (MINOS): A dose-finding study. Stroke 2010;41:2283-7. |
| 62. | Murata Y, Rosell A, Scannevin RH, Rhodes KJ, Wang X, Lo EH. Extension of the thrombolytic time window with minocycline in experimental stroke. Stroke 2008;39:3372-7. |
| 63. | Padma MV, Bhasin A, Bhatia R, Garg A, Gaikwad S, Prasad K, et al. Efficacy of minocycline in acute ischemic stroke: A single-blinded, placebocontrolled trial. Neurol India 2012;60:23-8. |
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