The Specific Requirements of Neural Repair Trials for Stroke

Novel molecular, cellular, and pharmacological therapies to stimulate repair of sensorimotor circuits after stroke are entering clinical trials. Compared with acute neuroprotection and thrombolysis studies, clinical trials for repair in subacute and chronic hemiplegic participants have a different time course for delivery of an intervention, different mechanisms of action within the milieu of the injury, distinct relationships to the amount of physical activity and skills practice of participants, and need to include more refined outcome measures. This review examines the biological interaction of targeted rehabilitation with neural repair strategies to optimize outcomes. We suggest practical guidelines for the incorporation of inexpensive skills training and exercise at home. In addition, we describe some novel outcome measurement tools, including wearable sensors, to obtain the more detailed outcomes that may identify at least some minimal level of success from cellular and regeneration interventions. Thus, proceeding in the shadow of acute stroke trial designs may unnecessarily limit the mechanisms of action of new repair strategies, reduce their impact on participants, and risk missing important behavioral outcomes.

[1]  John H. Martin,et al.  Electrical Stimulation of Motor Cortex in the Uninjured Hemisphere after Chronic Unilateral Injury Promotes Recovery of Skilled Locomotion through Ipsilateral Control , 2014, The Journal of Neuroscience.

[2]  G. Raisman,et al.  Transplantation of Autologous Olfactory Ensheathing Cells in Complete Human Spinal Cord Injury , 2013, Cell transplantation.

[3]  Andrew E Moran,et al.  Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990–2010: findings from the Global Burden of Disease Study 2010 , 2013, The Lancet. Global health.

[4]  Mariam Alaverdashvili,et al.  A behavioral method for identifying recovery and compensation: Hand use in a preclinical stroke model using the single pellet reaching task , 2013, Neuroscience & Biobehavioral Reviews.

[5]  D. Corbett,et al.  Efficacy of Rehabilitative Experience Declines with Time after Focal Ischemic Brain Injury , 2004, The Journal of Neuroscience.

[6]  Gert Kwakkel,et al.  Susceptibility to Deterioration of Mobility Long-Term After Stroke: A Prospective Cohort Study , 2006, Stroke.

[7]  Sandro Scattareggia Marchese,et al.  Community-Based Exercise for Upper Limb Paresis , 2014, Neurorehabilitation and neural repair.

[8]  B. Reynolds.  Stem Cell Therapies as an Emerging Paradigm in Stroke (STEPS): Bridging Basic and Clinical Science for Cellular and Neurogenic Factor Therapy in Treating Stroke , 2009, Stroke.

[9]  Matthew A Petoe,et al.  Proportional recovery after stroke depends on corticomotor integrity , 2015, Annals of neurology.

[10]  Marta P Pereira,et al.  Transplanted Stem Cell‐Secreted Vascular Endothelial Growth Factor Effects Poststroke Recovery, Inflammation, and Vascular Repair , 2011, Stem cells.

[11]  S. Dunnett.  Neural tissue transplantation, repair, and rehabilitation. , 2013, Handbook of clinical neurology.

[12]  B. Dobkin,et al.  SIRRACT , 2015, Neurorehabilitation and neural repair.

[13]  Koen Putman,et al.  Functional and Motor Outcome 5 Years After Stroke Is Equivalent to Outcome at 2 Months: Follow-Up of the Collaborative Evaluation of Rehabilitation in Stroke Across Europe , 2015, Stroke.

[14]  O. Lindvall,et al.  Stem cell repair of striatal ischemia. , 2012, Progress in brain research.

[15]  S. Barbay,et al.  Combination of NEP 1-40 Treatment and Motor Training Enhances Behavioral Recovery After a Focal Cortical Infarct in Rats , 2010, Stroke.

[16]  P. Langhorne,et al.  Physical rehabilitation approaches for the recovery of function and mobility following stroke. , 2014, The Cochrane database of systematic reviews.

[17]  Andreas Daffertshofer,et al.  Generalisability of the proportional recovery model for the upper extremity after an ischaemic stroke , 2017 .

[18]  G. Lynch,et al.  AMPA Receptor-Induced Local Brain-Derived Neurotrophic Factor Signaling Mediates Motor Recovery after Stroke , 2011, The Journal of Neuroscience.

[19]  Bruce H Dobkin,et al.  Body-weight-supported treadmill rehabilitation after stroke. , 2011, The New England journal of medicine.

[20]  B. Dobkin.  Wearable motion sensors to continuously measure real-world physical activities. , 2013, Current opinion in neurology.

[21]  T. Olsen,et al.  Outcome and time course of recovery in stroke. Part II: Time course of recovery. The Copenhagen Stroke Study. , 1995, Archives of physical medicine and rehabilitation.

[22]  J. P. Miller,et al.  Effect of constraint-induced movement therapy on upper extremity function 3 to 9 months after stroke: the EXCITE randomized clinical trial. , 2006, JAMA.

[23]  S. Carmichael,et al.  Plasticity in the Injured Brain , 2014, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[24]  T. Olsen,et al.  Outcome and time course of recovery in stroke. Part I: Outcome. The Copenhagen Stroke Study. , 1995, Archives of physical medicine and rehabilitation.

[25]  J. Kleim,et al.  Motor training induces experience-specific patterns of plasticity across motor cortex and spinal cord. , 2006, Journal of applied physiology.

[26]  Marie Johnston,et al.  Mental practice with motor imagery in stroke recovery: randomized controlled trial of efficacy , 2011, Brain : a journal of neurology.

[27]  Tommaso Pizzorusso,et al.  Perilesional treatment with chondroitinase ABC and motor training promote functional recovery after stroke in rats. , 2015, Cerebral cortex.

[28]  Bruce H Dobkin,et al.  The Promise of mHealth , 2011, Neurorehabilitation and neural repair.

[29]  O. Lindvall,et al.  Human induced pluripotent stem cell-derived cortical neurons integrate in stroke-injured cortex and improve functional recovery. , 2013, Brain : a journal of neurology.

[30]  D. Corbett,et al.  Enriched environment enhances transplanted subventricular zone stem cell migration and functional recovery after stroke , 2007, Neuroscience.

[31]  M. Schwab,et al.  Finding an optimal rehabilitation paradigm after stroke: enhancing fiber growth and training of the brain at the right moment. , 2014, Frontiers in human neuroscience.

[32]  J. Kleim,et al.  Exercise induces angiogenesis but does not alter movement representations within rat motor cortex , 2002, Brain Research.

[33]  F. Chollet,et al.  Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial , 2011, The Lancet Neurology.

[34]  J. Peduzzi,et al.  Olfactory Mucosal Autografts and Rehabilitation for Chronic Traumatic Spinal Cord Injury , 2010, Neurorehabilitation and neural repair.

[35]  W. Robberecht,et al.  Modifying expression of EphA4 and its downstream targets improves functional recovery after stroke. , 2013, Human molecular genetics.

[36]  Ju Lu,et al.  REPETITIVE MOTOR LEARNING INDUCES COORDINATED FORMATION OF CLUSTERED DENDRITIC SPINES IN VIVO , 2012, Nature.

[37]  J. Krakauer,et al.  Neurorehabilitation and Neural Repair Inter-individual Variability in the Capacity for Motor Recovery after Ischemic Stroke Neurorehabilitation and Neural Repair Additional Services and Information for Inter-individual Variability in the Capacity for Motor Recovery after Ischemic Stroke , 2022 .

[38]  Egle Cekanaviciute,et al.  Delayed Administration of a Small Molecule Tropomyosin-Related Kinase B Ligand Promotes Recovery After Hypoxic–Ischemic Stroke , 2012, Stroke.

[39]  P. Langhorne,et al.  Physical Rehabilitation Approaches for the Recovery of Function and Mobility After Stroke: Major Update , 2014 .

[40]  Ajmal Zemmar,et al.  Neutralization of Nogo-A Enhances Synaptic Plasticity in the Rodent Motor Cortex and Improves Motor Learning in Vivo , 2014, The Journal of Neuroscience.

[41]  S. Cramer,et al.  The case for modality-specific outcome measures in clinical trials of stroke recovery-promoting agents. , 2007, Stroke.

[42]  R. Croft.  A prospective cohort study comes of age. , 2000, Leprosy review.

[43]  M. Schwab,et al.  How Plastic Is the Brain after a Stroke? , 2014, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[44]  Bruce H Dobkin,et al.  New Evidence for Therapies in Stroke Rehabilitation , 2013, Current Atherosclerosis Reports.

[45]  M. Enserink.  Selling the Stem Cell Dream , 2006, Science.

[46]  Jeff Biernaskie,et al.  Neurobiology of Disease Efficacy of Rehabilitative Experience Declines with Time after Focal Ischemic Brain Injury , 2004 .

[47]  Ivo D Dinov,et al.  A role for ephrin-A5 in axonal sprouting, recovery, and activity-dependent plasticity after stroke , 2012, Proceedings of the National Academy of Sciences.

[48]  Marc Bolliger,et al.  Changes in Strength, Sensation, and Prehension in Acute Cervical Spinal Cord Injury , 2015, Neurorehabilitation and neural repair.

[49]  I. Módy,et al.  Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. , 2010, Nature.

[50]  Grant D. Huang,et al.  Robot-assisted therapy for long-term upper-limb impairment after stroke. , 2010, The New England journal of medicine.

[51]  S. Studenski,et al.  Prediction of responders for outcome measures of locomotor Experience Applied Post Stroke trial. , 2014, Journal of rehabilitation research and development.

[52]  M. Levin,et al.  What Do Motor “Recovery” and “Compensation” Mean in Patients Following Stroke? , 2009, Neurorehabilitation and neural repair.

[53]  J. Krakauer,et al.  Getting Neurorehabilitation Right , 2012, Neurorehabilitation and neural repair.

[54]  M. Chopp,et al.  Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation , 2012, The Lancet Neurology.

[55]  George S Mack,et al.  ReNeuron and StemCells get green light for neural stem cell trials , 2011, Nature Biotechnology.