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      Long-Term Paired Associative Stimulation Enhances Motor Output of the Tetraplegic Hand

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          Abstract

          A large proportion of spinal cord injuries (SCI) are incomplete. Even in clinically complete injuries, silent non-functional connections can be present. Therapeutic approaches that can strengthen transmission in weak neural connections to improve motor performance are needed. Our aim was to determine whether long-term delivery of paired associative stimulation (PAS, a combination of transcranial magnetic stimulation [TMS] with peripheral nerve stimulation [PNS]) can enhance motor output in the hands of patients with chronic traumatic tetraplegia, and to compare this technique with long-term PNS. Five patients (4 males; age 38–68, mean 48) with no contraindications to TMS received 4 weeks (16 sessions) of stimulation. PAS was given to one hand and PNS combined with sham TMS to the other hand. Patients were blinded to the treatment. Hands were selected randomly. The patients were evaluated by a physiotherapist blinded to the treatment. The follow-up period was 1 month. Patients were evaluated with Daniels and Worthingham's Muscle Testing (0–5 scale) before the first stimulation session, after the last stimulation session, and 1 month after the last stimulation session. One month after the last stimulation session, the improvement in the PAS-treated hand was 1.02 ± 0.17 points ( p < 0.0001, n = 100 muscles from 5 patients). The improvement was significantly higher in PAS-treated than in PNS-treated hands (176 ± 29%, p = 0.046, n = 5 patients). Long-term PAS might be an effective tool for improving motor performance in incomplete chronic SCI patients. Further studies on PAS in larger patient cohorts, with longer stimulation duration and at earlier stages after the injury, are warranted.

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          Most cited references23

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          Incidence of Spinal Cord Injury Worldwide: A Systematic Review

          Background: Incidence studies of spinal cord injury (SCI) are important for health-care planning and epidemiological research. This review gives a quantitative update on SCI epidemiology worldwide through a statistical evaluation of incidence rates. Methods: A systematic review was conducted. For each study, the crude rate ratio was calculated and, when possible, age- and gender-adjusted incidence rate ratios with 95% CI were determined by direct adjustment or using Poisson regression. Results: Thirteen studies were included. Annual crude incidence rates in traumatic SCI varied from 12.1 per million in The Netherlands to 57.8 per million in Portugal. Compared to the Portuguese reference study, incidence rates showed a 3-fold variation, with the highest rates in Canada and Portugal. Most traumatic SCI studies showed a bimodal age distribution. The first peak was found in young adults between 15 and 29 years and a second peak in older adults (mostly ≧65 years). Motor vehicle accidents and falls were the most prevalent causes of injury accounting for nearly equal percentages. In contrast, another age pattern in non-traumatic SCI reflected steadily increasing incidence with advancing age. Conclusions: The results show significant variation in SCI incidence with changing epidemiological patterns. A trend towards increased incidence in the elderly was observed, likely due to falls and non-traumatic injury.
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            Mechanisms underlying recovery of motor function after stroke.

            Stroke is the leading cause of long-term disability worldwide and a condition for which there is no universally accepted treatment. The development of new effective therapeutic strategies relies on a better understanding of the mechanisms underlying recovery of function. Noninvasive techniques to study brain function, including functional magnetic resonance imaging, positron emission tomography, transcranial magnetic stimulation, electroencephalography, and magnetoencephalography, led to recent studies that identified some of these operating mechanisms, resulting in the formulation of novel approaches to motor rehabilitation.
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              Electrical Stimulation to Enhance Axon Regeneration After Peripheral Nerve Injuries in Animal Models and Humans.

              Injured peripheral nerves regenerate their lost axons but functional recovery in humans is frequently disappointing. This is so particularly when injuries require regeneration over long distances and/or over long time periods. Fat replacement of chronically denervated muscles, a commonly accepted explanation, does not account for poor functional recovery. Rather, the basis for the poor nerve regeneration is the transient expression of growth-associated genes that accounts for declining regenerative capacity of neurons and the regenerative support of Schwann cells over time. Brief low-frequency electrical stimulation accelerates motor and sensory axon outgrowth across injury sites that, even after delayed surgical repair of injured nerves in animal models and patients, enhances nerve regeneration and target reinnervation. The stimulation elevates neuronal cyclic adenosine monophosphate and, in turn, the expression of neurotrophic factors and other growth-associated genes, including cytoskeletal proteins. Electrical stimulation of denervated muscles immediately after nerve transection and surgical repair also accelerates muscle reinnervation but, at this time, how the daily requirement of long-duration electrical pulses can be delivered to muscles remains a practical issue prior to translation to patients. Finally, the technique of inserting autologous nerve grafts that bridge between a donor nerve and an adjacent recipient denervated nerve stump significantly improves nerve regeneration after delayed nerve repair, the donor nerves sustaining the capacity of the denervated Schwann cells to support nerve regeneration. These reviewed methods to promote nerve regeneration and, in turn, to enhance functional recovery after nerve injury and surgical repair are sufficiently promising for early translation to the clinic.
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                Author and article information

                Journal
                J Neurotrauma
                J. Neurotrauma
                neu
                Journal of Neurotrauma
                Mary Ann Liebert, Inc. (140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA )
                0897-7151
                1557-9042
                15 September 2017
                15 September 2017
                15 September 2017
                : 34
                : 18
                : 2668-2674
                Affiliations
                [ 1 ]BioMag Laboratory, HUS Medical Imaging Center, University of Helsinki and Helsinki University Hospital , Helsinki, Finland.
                [ 2 ]Validia Rehabilitation Center , Helsinki, Finland.
                [ 3 ]Clinical Neurosciences, Clinical Neurophysiology, HUS Medical Imaging Center, University of Helsinki and Helsinki University Hospital , Helsinki, Finland.
                [ 4 ]Department of Physics, University of Helsinki , Helsinki, Finland.
                [ 5 ]Department of Radiology, HUS Medical Imaging Center, University of Helsinki and Helsinki University Hospital , Helsinki, Finland.
                [ 6 ]Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital , Helsinki, Finland.
                Author notes
                Address correspondence to: Anastasia Shulga, MD, PhD, BioMag Laboratory, HUS Medical Imaging Center, Helsinki University Central Hospital, PO Box 340, FI-00029 HUS, Finland

                E-mail: anastasia.shulga@ 123456helsinki.fi
                Article
                10.1089/neu.2017.4996
                10.1089/neu.2017.4996
                5610384
                28635523
                940750a1-9180-4572-855d-a48a8377ad73
                ©Aleksandra Tolmacheva et al., 2017; Published by Mary Ann Liebert, Inc.

                This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

                History
                Page count
                Figures: 2, Tables: 3, References: 32, Pages: 7
                Categories
                Original Articles

                paired associative stimulation,peripheral electrical stimulation,plasticity,spinal cord injury,transcranial magnetic stimulation

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