Restorative Neurology and Neuroscience - Volume 37, issue 4

Authors: Kleene, Ralf | Loers, Gabriele | Jakovcevski, Igor | Mishra, Bibhudatta | Schachner, Melitta

Article Type: Research Article

Abstract: Background: We have shown that histone H1 is a binding partner for polysialic acid (PSA) and that it improves functional recovery, axon regrowth/sprouting, and target reinnervation after mouse femoral nerve injury. Objective: Here, we analyzed whether histone H1 affects functional recovery, axon regrowth/sprouting, and target reinnervation after spinal cord injury of adult mice. Furthermore, we tested in vitro histone H1’s effect on astrocytic gene expression, cell shape and migration as well as on cell survival of cultured motoneurons. Methods: We applied histone H1 to compressed spinal cord and determined functional recovery and number of fibrillary …acidic protein (GFAP)- and neuron-glial antigen 2 (NG2)- positive glial cells, which contribute to glial scarring. Histone H1’s effect on migration of astrocytes, astrocytic gene expression and motoneuronal survival was determined using scratch-wounded astroglial monolayer cultures, astrocyte cultures for microarray analysis, and motoneuron cell culture under oxidative stress conditions, respectively. Results: Histone H1 application improves locomotor functions and enhances monoaminergic and cholinergic reinnervation of the spinal cord. Expression levels of GFAP and NG2 around the lesion site were decreased in histone H1-treated mice relative to vehicle-treated mice six weeks after injury. Histone H1 reduced astrocytic migration, changed the shape of GFAP- and NG2-positive glial cells and altered gene expression. Gene ontology enrichment analysis indicated that in particular genes coding for proteins involved in proliferation, differentiation, migration and apoptosis are dysregulated. The up- and down-regulation of distinct genes was confirmed by qPCR and Western blot analysis. Moreover, histone H1 reduced hydrogen peroxide-induced cell death of cultured motoneurons. Conclusions: The combined observations indicate that histone H1 locally applied to the lesion site, improves regeneration after spinal cord injury. Some of these beneficial functions of histone H1 in vivo and in vitro can be attributed to its interaction with PSA-carrying neural cell adhesion molecule. Show more

Keywords: Glial scar, histone H1, polysialic acid, mouse spinal cord injury, synaptic plasticity, regeneration, locomotion, axonal regrowth, astrogliosis, migration

DOI: 10.3233/RNN-190903

Citation: Restorative Neurology and Neuroscience, vol. 37, no. 4, pp. 291-313, 2019

Authors: Wang, Huibin | Cheng, Xi | Yu, Hang | Zhang, Xiuchun | Guan, Meiting | Zhao, Lanqing | Liu, Yang | Linag, Yifan | Luo, Yujia | Zhao, Chuansheng

Article Type: Research Article

Abstract: Background: GABAA receptors modulate the behavioral recovery encountered in both experimental animals and patients with ischemic injury, possibly through promoting structural plasticity. We hypothesized that activation of GABAA receptors would regulate axonal growth, which in turn would improve the behavioral recovery in ischemic rats. Objective: To investigate the effects of muscimol on axonal growth, synaptic plasticity and behavioral performance in rats after a focal ischemia induced by endothelin-1 (ET-1). Methods: Focal ischemic infarct was induced by ET-1. The rats were randomly divided into 3 groups: sham-operated group, ischemic group, ischemic+muscimol group. The muscimol infusion …into contralateral cortex started on post-operative day 7 continuing until day 21. Biotinylated dextran amine was injected on post-operative day 14 into the contralesional motor cortex to trace the crossing corticospinal tract fibers. The expression levels of growth inhibitors, Nogo receptor, NogoA, RhoA, and Rho-associated kinase were measured in the peri-infarct cortex. The expressions of vGlut-1 and postsynaptic density-95 were measured by immunohistochemistry and Western blot in the denervated spinal cord. The behavioral recovery was evaluated by sensorimotor tests on post-operative days 32–34. Results: Treatment with the specific GABAA receptors agonist, muscimol, did not increase axonal growth into the denervated hemispheres and spinal cord after stroke. However, the activation of GABAA receptors partially improved the rats’ behavioral performance after the ET-1-induced stroke. Conclusions: Our study revealed that infusion of muscimol into the contralateral motor cortex during the repair stage could partially improve the behavioral performances without promoting axonal growth from uninjured hemisphere motor cortex to the denervated striatum and spinal cord, nor did it prevent the expression of axonal growth inhibitors in peri-lesioned cortex. More detailed studies will be required to clarify the role of GABAA Rs in regulating the behavioral recovery after a stroke. Show more

Keywords: Muscimol, GABAA receptors, axonal growth, stroke, behavioral recovery

DOI: 10.3233/RNN-180827

Citation: Restorative Neurology and Neuroscience, vol. 37, no. 4, pp. 315-331, 2019

Authors: Beaulieu, Louis-David | Blanchette, Andréanne K. | Mercier, Catherine | Bernard-Larocque, Vincent | Milot, Marie-Hélène

Article Type: Research Article

Abstract: Background: Transcranial direct current stimulation (tDCS) is a promising tool for stroke rehabilitation. Yet, so far, results from the available clinical trials are inconclusive. Objectives: The primary objective of the present work was to test the efficacy of multiple sessions of tDCS combined with a highly standardized and progressive resistance training program of the affected upper limb in individuals in the chronic phase of recovery after a stroke. Secondary objectives were to test the safety and tolerability of these combined interventions. Methods: This two-arm parallel pilot trial recruited participants that were ≥18 years old, community-dwelling, and …had sustained a supratentorial stroke ≥6 months prior to the study. They were allocated using a stratified randomization into two groups: 1) real tDCS + resistance training and 2) sham tDCS + resistance training. The resistance training program targeted the affected upper limb and consisted in 60 minutes of exercises, 3 times/week over 4 weeks. During each session, participants received either real- or sham-tDCS, using a bi-hemispheric montage for the first 20 minutes, and were blinded to the tDCS intervention. Outcome measures of clinical efficacy (Fugl-Meyer Assessment, Box and Block Test, Wolf Motor Function Test, grip strength, modified Ashworth scale and Motor Activity Log) were assessed by a blinded evaluator before and after the 4-week training program. Safety and tolerability were evaluated, respectively, by the number and characteristics of tDCS adverse events and dropout rates with their reasons. Results: From the 147 individuals screened for eligibility, 14 participants (68.9±10.0 years old; 70.9±57.6 months post-stroke) met the selection criteria and were allocated to real-tDCS (n  = 7) or sham-tDCS (n  = 7) groups. Both groups improved on the clinical outcome measures, but these changes were not significantly different between groups (p  > 0.17). No dropout occurred throughout the study. Participants frequently reported mild skin tingling during the administration of both real- and sham-tDCS, and no group difference was noted for its frequency and intensity (p  > 0.38). One participant having received real-tDCS complained about a mild skin burning sensation after two sessions. The a priori sample size analysis performed on the Fugl-Meyer Assessment scores revealed that 56 participants would be required in a future clinical trial to reach 80% power at a significance level of 0.05. Conclusions: In this pilot study, repeated sessions of bi-hemispheric tDCS coupled with resistance training were found safe and tolerable for individuals at the chronic phase post-stroke. However, the use of tDCS did not result in additional sensorimotor improvements when compared to sham-tDCS. Further research is needed to better assess the clinical benefits of combining non-invasive transcranial stimulation with rehabilitation after a stroke. Show more

Keywords: Transcranial direct current stimulation, resistance training, treatment outcome, stroke rehabilitation

DOI: 10.3233/RNN-190908

Citation: Restorative Neurology and Neuroscience, vol. 37, no. 4, pp. 333-346, 2019

Authors: Moore, T.L. | Bowley, B.G.E. | Pessina, M.A. | Calderazzo, S.M. | Medalla, M. | Go, V. | Zhang, Z.G. | Chopp, M. | Finklestein, S. | Harbaugh, A.G. | Rosene, D.L. | Buller, B.

Article Type: Research Article

Abstract: Background: Exosomes from mesenchymal stromal cells (MSCs) are endosome-derived vesicles that have been shown to enhance functional recovery in rodent models of stroke. Objective: Building on these findings, we tested exosomes as a treatment in monkeys with cortical injury. Methods: After being trained on a task of fine motor function of the hand, monkeys received a cortical injury to the hand representation in primary motor cortex. Twenty-four hours later and again 14 days after injury, monkeys received exosomes or vehicle control. Recovery of motor function was followed for 12 weeks. Results: Compared to monkeys …that received vehicle, exosome treated monkeys returned to pre-operative grasp patterns and latency to retrieve a food reward in the first three-five weeks of recovery. Conclusions: These results provide evidence that in monkeys exosomes delivered after cortical injury enhance recovery of motor function. Show more

Keywords: Exosomes, cortical injury, recovery, rhesus monkey

DOI: 10.3233/RNN-190910

Citation: Restorative Neurology and Neuroscience, vol. 37, no. 4, pp. 347-362, 2019

Authors: Krishnan, Chandramouli

Article Type: Research Article

Abstract: Background: Short interval intracortical inhibition (SICI) is commonly used to assess inhibition in the motor cortex and is known to be affected by the paired-pulse stimulus parameters (i.e., interstimulus interval [ISI], conditioning stimulus intensity [CSI] and test stimulus intensity [TSI]) used during testing. While the effects of stimulus parameters are well-studied in the upper-extremity, evidence in the lower-extremity is lacking. Objective: To comprehensively examine the effects of alterations in paired-pulse stimulus parameters on the two phases of SICI in the quadriceps muscle group. Methods: Seventeen adults (8 males, 9 females) volunteered to participate in this study. …SICI was examined over a range of CSIs (70–90% active motor threshold [AMT]), TSIs (100–140% AMT), and ISIs (1.0–3.0 ms) using both EMG and torque responses elicited by transcranial magnetic stimulation (TMS). Results: The results indicated that SICI at 1.0 ms ISI was best revealed with a CSI of 70% and TSI ≥110% AMT, whereas SICI at 2.5 ms ISI was best revealed with a CSI of 80–90% and a TSI of ≥130% AMT. Unlike upper-extremity muscles, evaluating SICI with a CSI of 70% AMT and an ISI of 1.0 ms produced the greatest inhibition for all TSIs. In general, inhibitory effects were contaminated by facilitatory effects when using a TSI of 100% AMT. Conclusions: The amount of inhibition was dependent on the stimulation parameters used during testing. A CSI of 70% AMT, ISI of 1.0 ms, and TSI of ≥110% AMT appear to be optimal for measuring SICI in the quadriceps muscle; however, other parameters can be used if careful consideration is given to the described interaction between the parameters. Show more

Keywords: Cortical excitability, knee, paired-pulse stimulation, two phases, twitch, bayesian

DOI: 10.3233/RNN-180894

Citation: Restorative Neurology and Neuroscience, vol. 37, no. 4, pp. 363-374, 2019

Authors: Orgah, John Owoicho | Ren, Jie | Liu, Xinyan | Orgah, Emmanuel A. | Gao, Xiu Mei | Zhu, Yan

Article Type: Research Article

Abstract: This article has been retracted, and the online PDF has been watermarked “RETRACTED”. A retraction notice is available at DOI: 10.3233/RNN-239001 .

DOI: 10.3233/RNN-180828

Citation: Restorative Neurology and Neuroscience, vol. 37, no. 4, pp. 375-395, 2019

Authors: Tao, Dongxia | Liu, Fangxi | Sun, Xiaoyu | Qu, Huiling | Zhao, Shanshan | Zhou, Zhike | Xiao, Ting | Zhao, Chuansheng | Zhao, Mei

Article Type: Research Article

Abstract: Stroke often leads to neuronal injury and neurological functional deficits. Whilst spontaneous neurogenesis and axon regeneration are induced by ischemic stroke, effective pharmacological treatments are also essential for the improvement of neuroplasticity and functional recovery after stroke. However, no pharmacological therapy has been demonstrated to be able to effectively improve the functional recovery after stroke. Bumetanide is a specific Na+ -K+ -Cl– co-transporter inhibitor which can maintain chloride homeostasis in neurons. Therefore, many studies have focused on this drug’s effect in stroke recovery in recent years. Here, we first review the function of Na+ -K+ -Cl– co-transporter in …neurons, then how bumetanide’s role in reducing brain damage, promoting neuroplasticity, leading to functional recovery after stroke, is elucidated. Finally, we discuss current limitations of bumetanide’s efficiency and their potential solutions. These results may provide new avenues for further exploring mechanisms of post-stroke functional recovery as well as promising therapeutic targets for functional disability rehabilitation after ischemic stroke. Show more

Keywords: Bumetanide, stroke, neural damage, neuroplasticity, functional recovery

DOI: 10.3233/RNN-190926

Citation: Restorative Neurology and Neuroscience, vol. 37, no. 4, pp. 397-407, 2019

Authors: Pei, Yu-Chen | Cheng, Yu-Po | Chen, Ji-Lin | Lin, Cheng-Hung | Wen, Chih-Jen | Huang, Jian-Jia

Article Type: Research Article

Abstract: Background: Nerve reconstructive surgery induces a transient loss and a prolonged and a gradual return of sensory inputs to the brain. It is unknown whether, following this massive peripheral denervation, the brain will experience a prolonged period of severe, intrinsic dysfunction. Objective: We aim to investigate the mechanisms of return of processing function in cortical neurons. Methods: We used the whisker model in rats to evaluate the functional recovery in the somatosensory cortex after a nerve reconstruction surgery. Multi-unit recording in the barrel cortex was performed in lightly anesthetized rats while their whiskers were stimulated by …a whisker stimulator. Results: We observed a loss of neuronal responses to whisker stimulation 1 week after surgery, which started to recover 2 weeks after surgery. Following the surgery, only 11.8% of units had principle whiskers (PWs) returned to their original status while 17.7% had PWs different from their original status, indicating the effect of aberrant reinnervation on the whisker response map. Conclusions: Robust neuronal responses to sensory stimulation even when only sparse sensory inputs are available in the early recovery phase. During this phase, aberrant reinnervation induces disorganized whisker tuning, a finding that might be account for the hypoesthesia and paresthesia during early recovery after nerve reconstruction. Show more

Keywords: Barrel cortex, infraorbital nerve, neurorrhaphy, reconstruction surgery, whisker

DOI: 10.3233/RNN-190914

Citation: Restorative Neurology and Neuroscience, vol. 37, no. 4, pp. 409-419, 2019