Restorative Neurology and Neuroscience - Volume 27, issue 1

Authors: Guzen, Fausto Pierdoná | de Almeida Leme, Ricardo José | de Andrade, Michele Schultz Ramos | de Luca and, Bianca Aparecida | Chadi, Gerson

Article Type: Research Article

Abstract: Purpose: The aversive nature of regenerative milieu is the main problem related to the failure of neuronal restoration in the injured spinal cord which however might be addressed with an adequate repair intervention. We evaluated whether glial cell line-derived neurotrophic factor (GDNF) may increase the ability of sciatic nerve graft, placed in a gap promoted by complete transections of the spinal cord, to enhance motor recovery and local fiber growth. Methods: Rats received a …4 mm-long gap at low thoracic level and were repaired with a fragment of the sciatic nerve. GDNF was added (NERVE±GDNF) or not to the grafts (NERVE--GDNF). Motor behavior score (BBB) and sensorimotor tests-linked to the combined behavior score (CBS), which indicate the degree of the motor improvement and the percentage of functional deficit, respectively, and also the spontaneous motor behavior in an open field by means of an infrared motion sensor activity monitor were analyzed. At the end of the third month post surgery, the tissue composed by the graft and the adjacent regions of the spinal cord was removed and submitted to the immunohistochemistry of the neurofilament-200 (NF-200), growth associated protein-43 (GAP-43), microtubule associated protein-2 (MAP-2), 5-hidroxytryptamine (serotonin, 5-HT) and calcitonin gene related peptide (CGRP). The immunoreactive fibers were quantified at the epicenter of the graft by means of stereological procedures. Results: Higher BBB and lower CBS levels (p < 0.001) were found in NERVE±GDNF rats. GDNF added to the graft increased the levels of individual sensorimotor tests mainly at the third month. Analysis of the spontaneous motor behavior showed decreases in the time and number of small movement events by the third month without changes in time and number of large movement events in the NERVE$+$GDNF rats. Immunoreactive fibers were encountered inside the grafts and higher amounts of NF-200, GAP-43 and MAP-2 fibers were found in the epicenter of the graft when GDNF was added. A small amount of descending 5-HT fibers was seen reentering in the adjacent caudal levels of the spinal cords which were grafted in the presence of GDNF, event that has not occurred without the neurotrophic factor. GDNF in the graft also led to a large amount of MAP-2 perikarya and fibers in the caudal levels of the cord gray matter, as determined by the microdensitometric image analysis. Conclusions: GDNF added to the nerve graft favored the motor recovery, local neuronal fiber growth and neuroplasticity in the adjacent spinal cord. Show more

Keywords: Neuroregeneration, sciatic nerve graft, spinal cord, glial cell line-derived neurotrophic factor, neuroprotection, motor behavior, repair

DOI: 10.3233/RNN-2009-0454

Citation: Restorative Neurology and Neuroscience, vol. 27, no. 1, pp. 1-16, 2009

Authors: Cauraugh, James H. | Coombes, Stephen A. | Lodha, Neha | Naik, Sagar K. | Summers, Jeffery J.

Article Type: Research Article

Abstract: Background: The current treatment intervention study determined the effect of coupled bilateral training (i.e., bilateral movements and EMG-triggered neuromuscular stimulation) and resistive load (mass) on upper extremity motor recovery in chronic stroke. Methods: Thirty chronic stroke subjects were randomly assigned to one of three behavioral treatment groups and completed 6 hours of rehabilitation in 4 days: (1) coupled bilateral training with a load on the unimpaired hand, (2) coupled bilateral training with no load …on the unimpaired hand, and (3) control (no stimulation assistance or load). Results: Separate mixed design ANOVAs revealed improved motor capabilities by the coupled bilateral groups. From the pretest to the posttest, both the coupled bilateral no load and load groups moved a higher number of blocks and demonstrated more regularity in the sustained contraction task. Faster motor reaction times across test sessions for the coupled bilateral load group provided additional evidence for improved motor capabilities. Conclusions: Together these behavioral findings lend support to the contribution of coupled bilateral training with a load on the unimpaired arm to improved motor capabilities on the impaired arm. This evidence supports a neural explanation in that simultaneously moving both limbs during stroke rehabilitation training appears to activate balanced interhemispheric interactions while an extra load on the unimpaired limb provides stability to the system. Show more

Keywords: Chronic stroke, neurological rehabilitation, bilateral movement training, EMG-triggered neuromuscular stimulation, motor recovery

DOI: 10.3233/RNN-2009-0455

Citation: Restorative Neurology and Neuroscience, vol. 27, no. 1, pp. 17-25, 2009

Authors: Müller, Harald D. | Neder, Angelika | Sommer, Clemens | Schäbitz, Wolf-Rüdiger

Article Type: Research Article

Abstract: Purpose: Recent data indicate that both brain-derived neurotrophic factor (BDNF) and granulocyte-colony stimulating factor (G-CSF) exert substantial neuroregenerative effects and improve functional outcome after ischemic stroke. In the present study, we checked for potential differences in the postischemic modulation of various excitatory and inhibitory neurotransmitter receptors as well as various marker molecules for structural plasticity by BDNF versus G-CSF. Methods: Adult male Wistar rats were subjected to photothrombotic ischemia and …subsequently treated with NaCl, BDNF or G-CSF, respectively. After 6 weeks, postischemic protein expression of the NR1, GluR1 and α2 subunit of the NMDA, AMPA and GABA_{A} receptor, respectively, was semiquantitatively determined ipsi- and contralateral to the ischemic lesion. Structural plasticity was further analyzed immunohistochemically using antibodies against MAP1B, MAP2 and synaptophysin. Results: Only BNDF caused a significantly reduced postischemic protein expression of the GABA_{A} receptor α2 subunit and the NR1 subunit of the NMDA receptor in the hippocampus. Furthermore, BDNF compared to G-CSF increased MAP1B protein expression in the periischemic regenerative region. Conclusions: Although both BDNF and G-CSF have been shown to improve postischemic functional outcome to a similar extent, exogenous administration results in different underlying structural reorganization processes suggesting specific modulations of plasticity-associated events by these trophic factors. Show more

Keywords: Neurotransmitter receptors, regeneration, plasticity, growths factors, ischemia

DOI: 10.3233/RNN-2009-0459

Citation: Restorative Neurology and Neuroscience, vol. 27, no. 1, pp. 27-39, 2009

Authors: Yu, Guolong | Borlongan, Cesar V. | Stahl, Christine E. | Hess, David C. | Ou, Yali | Kaneko, Yuji | Yu, Seong Jin | Yang, Tianlun | Fang, Li | Xie, Xiumei

Article Type: Research Article

Abstract: Purpose: This review paper summarizes relevant studies, discusses potential mechanisms of transplanted cell-mediated neuroprotection, and builds a case for the need to establish outcome parameters that are critical for transplantation success. In particular, we outline the advantages and disadvantages of systemic delivery of human umbilical cord blood (HUCB) cells in the field of cellular transplantation for treating ischemic stroke. Methods: A MEDLINE/PubMed systematic search of published articles in peer-reviewed journals over the last 25 …years was performed focusing on the theme of HUCB as donor graft source for transplantation therapy in neurological disorders with emphasis on stroke. Results: Ischemic stroke remains a leading cause of human death and disability. Although stroke survivors may gain spontaneous partial functional recovery, they often suffer from sensory-motor dysfunction, behavioral/neurological alterations, and various degrees of paralysis. Currently, limited clinical intervention is available to prevent ischemic damage and restore lost function in stroke victims. Stem cells from fetal tissues, bone marrow, and HUCB has emerged in the last few years as a potential cell transplant cell source for ischemic stroke, because of their capability to differentiate into multiple cell types and the possibility that they may provide trophic support for cell survival, tissue repair, and functional recovery. Conclusion: A growing number of studies highlight the potential of systemic delivery of HUCB cells as a novel therapeutic approach for stroke. However, additional preclinical studies are warranted to reveal the optimal HUCB transplant regimen that is safe and efficacious prior to proceeding to large-scale clinical application of these cells for stroke therapy. Show more

Keywords: Cerebral ischemia, adult stem cells, transplantation, neuroprotection, neurorestoration

DOI: 10.3233/RNN-2009-0460

Citation: Restorative Neurology and Neuroscience, vol. 27, no. 1, pp. 41-54, 2009

Authors: Borich, Michael | Arora, Sanjeev | Kimberley, Teresa Jacobson

Article Type: Research Article

Abstract: Purpose: Focal hand dystonia (FHD) is a rare but potentially devastating disorder involving involuntary muscle spasms and abnormal posturing that impairs functional hand use. Increased cortical excitability and lack of inhibitory mechanisms have been associated with these symptoms. This study investigated the short- and long-term effects of repeated administrations of repetitive-transcranial magnetic stimulation (rTMS) on cortical excitability and handwriting performance. Methods: Six subjects with FHD and nine healthy controls were …studied. All subjects with FHD received rTMS (1Hz) to the premotor cortex (PMC) for five consecutive days; of those, three subjects received five days of sham rTMS completed ten days prior to real treatment. Healthy subjects received one real rTMS session. Cortical silent period (CSP) and measures of handwriting performance were compared before and after treatment and at ten-day post-treatment follow-up. Results: At baseline, significant differences in CSP and pen pressure were observed between subjects with FHD and healthy controls. Differences in CSP and pen velocity between subjects in real and sham rTMS groups were observed across treatment sessions and maintained at follow-up. Conclusions: After five days of rTMS to PMC, reduced cortical excitability and improved handwriting performance were observed and maintained at least ten days following treatment in subjects with FHD. These preliminary results support further investigation of the therapeutic potential of rTMS in FHD. Show more

Keywords: Writer's cramp, handwriting analysis, transcranial magnetic stimulation, rehabilitation, cortical excitability

DOI: 10.3233/RNN-2009-0461

Citation: Restorative Neurology and Neuroscience, vol. 27, no. 1, pp. 55-65, 2009

Authors: Lago, Natalia | Casas, Caty | Muir, Elizabeth M. | Rogers, John | Navarro, Xavier

Article Type: Research Article

Abstract: Purpose: By using a nerve amputee model of the rat sciatic nerve (Lago and Navarro, 2007), we have tested a strategy for the long-term maintenance of regenerated axons without distal target reinnervation, by grafting Schwann cells (SCs) into a capped silicone chamber containing the ending nerve stump. Methods: The sciatic nerve of rats was transected and repaired with a silicone tube, the distal nerve was again cut at 10 mm and inserted in a …capped tube that was filled with saline or with a suspension of cultured SCs. Transplants of SCs obtained from primary cultures have been compared with those of an immortalized SC line (SCTM41) or the same line overexpressing GDNF. Results: The histological results show that nerve fibers were able to regenerate through a short distal nerve segment ending into the capped chamber, and sustain distal branches without degenerating for several months. There was abundant axonal sprouting forming an ending neuroma, and the caliber of myelinated fibers remained far thinner than normal during the 9 months investigated. With a distal transplant of primary SCs there were significantly more regenerated myelinated fibers than in the control group at 9 months, indicating that the grafted cells stimulated the axonal growth response and helped to maintain survival of axon branches. In contrast, axonal regeneration was significantly reduced with grafts of SCTM41 cells, probably due to physical competition between cell proliferation and axonal growth. SCTM41 cells overexpressing GDNF improved the regenerative response with respect to the parent SCTM41 cells, although not to the same extent as the primary SCs. Conclusion: A graft of primary SCs in the capped chamber stimulated axonal growth response and/or maintained survival of axonal branches on the long term in the nerve amputee model. Show more

Keywords: Schwann cell, nerve regeneration, neuroma, axon sprouting, amputation, neural interfaces

DOI: 10.3233/RNN-2009-0462

Citation: Restorative Neurology and Neuroscience, vol. 27, no. 1, pp. 67-78, 2009