Restorative Neurology and Neuroscience - Volume 33, issue 2

Authors: Shin, Samuel S. | Grandhi, Ramesh | Henchir, Jeremy | Yan, Hong Q. | Badylak, Stephen F. | Dixon, C. Edward

Article Type: Research Article

Abstract: Purpose: In previous studies, collagen based matrices have been implanted into the site of lesion in different models of brain injury. We hypothesized that semisynthetic collagen matrix can have neuroprotective function in the setting of traumatic brain injury. Methods: Rats were subjected to sham injury or controlled cortical impact. They either received extracellular matrix graft (DuraGen) over the injury site or did not receive any graft and underwent beam balance/beam walking test at post injury days 1–5 and Morris water maze at post injury days 14–18. Animals were sacrificed at day 18 for tissue analysis. Results: Collagen matrix implantation in …injured rats did not affect motor function (beam balance test: p = 0.627, beam walking test: p = 0.921). However, injured group with collagen matrix had significantly better spatial memory acquisition (p < 0.05). There was a significant reduction in lesion volume, as well as neuronal loss in CA1 (p < 0.001) and CA3 (p < 0.05) regions of the hippocampus in injured group with collagen matrix (p < 0.05). Conclusions: Collagen matrix reduces contusional lesion volume, neuronal loss, and cognitive deficit after traumatic brain injury. Further studies are needed to demonstrate the mechanisms of neuroprotection by collagen matrix. Show more

Keywords: Collagen, matrix, traumatic brain injury, bioscaffold, neuroregeneration, neurorepair

DOI: 10.3233/RNN-140430

Citation: Restorative Neurology and Neuroscience, vol. 33, no. 2, pp. 95-104, 2015

Authors: Cancelli, Andrea | Cottone, Carlo | Zito, Giancarlo | Di Giorgio, Marina | Pasqualetti, Patrizio | Tecchio, Franca

Article Type: Research Article

Abstract: Purpose: Transcranial electric stimulations (tES) with amplitude-modulated currents are promising tools to enhance neuromodulation effects. It is essential to select the correct cortical targets and inhibitory/excitatory protocols to reverse changes in specific networks. We aimed at assessing the dependence of cortical excitability changes on the current amplitude of 20 Hz transcranial alternating current stimulation (tACS) over the bilateral primary motor cortex. Methods: We chose two amplitude ranges of the stimulations, around 25 μA/cm2 and 63 μA/cm2 from peak to peak, with three values (at steps of about 2.5%) around each, to generate, respectively, inhibitory and excitatory effects of …the primary motor cortex. We checked such changes online through transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs). Results: Cortical excitability changes depended upon current density (p = 0.001). Low current densities decreased MEP amplitudes (inhibition) while high current densities increased them (excitation). Conclusions: tACS targeting bilateral homologous cortical areas can induce online inhibition or excitation as a function of the current density. Show more

Keywords: Neuromodulation, transcranial alternating current stimulation (tACS), neuronavigation, motor cortex (M1), superficial current density, personalized electrode

DOI: 10.3233/RNN-140411

Citation: Restorative Neurology and Neuroscience, vol. 33, no. 2, pp. 105-114, 2015

Authors: Breitenstein, Caterina | Korsukewitz, Catharina | Baumgärtner, Annette | Flöel, Agnes | Zwitserlood, Pienie | Dobel, Christian | Knecht, Stefan

Article Type: Research Article

Abstract: Purpose: L-dopa has been shown to improve outcome of moderate-intensity language training after stroke in acute aphasia. Given the critical role of training intensity we probed the effect of l-dopa in combination with high-intensity language training in chronic post-stroke aphasia. Methods: In this prospective, randomized, placebo-controlled, double-blind study, aphasia patients (>1 year post stroke) were administered 100/25 mg of l-dopa/carbidopa or placebo daily prior to four hours of language training for two weeks. Conditions were crossed-over after a wash-out period of 4 weeks. Results: An a-priori planned interim analysis (n = 10) showed that naming performance and verbal communication improved …significantly and persistently for at least 6 months in every patient, but l-dopa had no incremental effect to intensive training. Conclusion: High-intensity language training in chronic aphasia may take learning to a ceiling that precludes additive benefits from l-dopa. Effects of l-dopa on post-stroke recovery during less intense treatment in chronic aphasia remain to be evaluated. Show more

Keywords: Stroke, aphasia, rehabilitation, l-dopa, intensive training

DOI: 10.3233/RNN-140435

Citation: Restorative Neurology and Neuroscience, vol. 33, no. 2, pp. 115-120, 2015

Authors: Pei, Yu-Cheng | Fang, Tuan-Jen | Hsin, Li-Jen | Li, Hsueh-Yu | Wong, Alice MK

Article Type: Research Article

Abstract: Purpose: To investigate the neurologic and functional effect of intracordal hyaluronate injections in acute unilateral vocal fold paralysis (UVFP) in a randomized controlled trial. Methods: In this open-label, randomized controlled study, 29 patients with UVFP were recruited within 6 months of their first outpatient visit and were randomized to receive either single hyaluronate injection (HI group) or conservative management (CM group). Quantitative laryngeal electromyography, videolaryngostroboscopy, UVFP-related quality of life (Voice Outcomes Survey, VOS), laboratory voice analysis, and health-related quality of life (SF-36) were evaluated at baseline, and at 1, 3 and 6 months post-injection in the HI group, and at …baseline and 6 months in the CM group. Results: Improvements in most quality of life domains and other assessments were comparable between the HI and CM groups; however, the HI group had a greater improvement in the mental health domain of quality of life at the end of follow-up. Conclusions: Early hyaluronate injection cannot improve nerve regeneration but can result in long-lasting improvements in patients' psychosocial well-being, thus highlighting the importance of early intervention for patients with UVFP. Show more

Keywords: Unilateral vocal fold paralysis, hyaluronate, injection laryngoplasty, glottal gap, quality of life, laryngeal electromyography

DOI: 10.3233/RNN-140439

Citation: Restorative Neurology and Neuroscience, vol. 33, no. 2, pp. 121-130, 2015

Authors: Chen, Xinran | Dang, Ge | Dang, Chao | Liu, Gang | Xing, Shihui | Chen, Yicong | Xu, Qiang | Zeng, Jinsheng

Article Type: Research Article

Abstract: Purpose: We aimed to develop a nonhuman primate (NHP) stroke model for studies of secondary lesions in remote areas and to characterize its behavioral and neuroimaging features. Methods: Monkeys were either subjected to middle cerebral artery occlusion (MCAO) distal to the M1 branch (n = 17) or sham operation (n = 7). Neurological assessment and magnetic resonance imaging (MRI) were performed before and 1 week after operation. Results: After MCAO, six monkeys showed occlusion of the distal M1 segment and infarcts predominantly in the cortical and subcortical regions, without hippocampal and thalamic involvement. They had obvious neurological deficits. The other …11 monkeys showed blockage of the main trunk of the MCA, with infarcts extending into the hippocampus and thalamus, but no substantia nigra involvement. Their infarct volume were larger and neurological deficits were more severe than those after distal M1 occlusion. All sham-operated monkeys displayed normal behavior; however, MRI revealed small infarcts in three animals. Conclusions: MCAO or even sham operations might cause cerebral infarction in NHPs. Therefore, neurological assessment should be combined with MRI for screening candidate stroke models. Our model is suitable for studying secondary damage in remote regions, including the thalamus, hippocampus, and substantia nigra, after stroke. Show more

Keywords: Nonhuman primates, middle cerebral artery occlusion, remote lesions, model, magnetic resonance imaging

DOI: 10.3233/RNN-140440

Citation: Restorative Neurology and Neuroscience, vol. 33, no. 2, pp. 131-142, 2015

Authors: Liu, Peng | Zou, Dan | Yi, Long | Chen, Mingliang | Gao, Yanxiang | Zhou, Rui | Zhang, Qianyong | Zhou, Yong | Zhu, Jundong | Chen, Ka | Mi, Mantian

Article Type: Research Article

Abstract: Purpose: Acute hypobaric hypoxia (HH) causes persistent cognitive impairment, affecting memory function specifically. Mitochondrial dysfunction and synaptic morphological change were the prominent pathological features of HH exposure on brain. Quercetin, a flavonoid found in fruits, vegetables, leaves and grains, is reported to prevent ischemia induced by neuronal injury. This study investigated the efficacy of quercetin to ameliorate HH-induced memory deficit. Methods: Rats were exposed to HH equivalent to 5000 m for 7 days in a decompression chamber and received quercetin daily (50, 75 or 100 mg/kg·bw) via gavage during the period of exposure. Cognitive performance was assessed by the Morris …water maze test. In vitro, the effect of quercetin was tested in hippocampus tissue. Results: Quercetin, especially at 100 mg/kg·bw, significantly reduced HH-induced memory decline. Meanwhile, HH-induced hippocampus mitochondrial and synaptic lesions were ameliorated by quercetin. Furthermore, quercetin regulated the expression of sirtuin 1(Sirt1), PGC-1α, and the proteins related with mitochondrial biogenesis and dynamics. Moreover, quercetin increased expression of fibronectin type III domain-containing protein 5 (FNDC5) and brain-derived neurotrophic factor (BDNF), showing the PGC-1α/FNDC5/BNDF pathways might be involved in neuronal adaptation. Conclusions: The results suggest quercetin has prophylactic potential for amelioration of HH-induced memory impairment, which is associated with the mitochondrial and neuronal adaptation in hippocampus. Show more

Keywords: Hypobaric hypoxia, memory impairment, mitochondria, neuroprotection, PGC-1α, quercetin

DOI: 10.3233/RNN-140446

Citation: Restorative Neurology and Neuroscience, vol. 33, no. 2, pp. 143-157, 2015

Authors: Naro, Antonino | Calabrò, Rocco Salvatore | Russo, Margherita | Leo, Antonino | Pollicino, Patrizia | Quartarone, Angelo | Bramanti, Placido

Article Type: Research Article

Abstract: Purpose: Disorders of consciousness (DOC) diagnosis relies on the presence or absence of purposeful motor responsiveness, which characterizes the minimally conscious state (MCS) and the unresponsive wakefulness syndrome (UWS), respectively. Functional neuroimaging studies have raised the question of possible residual conscious awareness also in clinically-defined UWS patients. The aim of our study was to identify electrophysiological parameters, by means of a transcranial magnetic stimulation approach, which might potentially express the presence of residual networks sustaining fragmentary behavioral patterns, even when no conscious behavior can be observed. Methods: We enrolled 25 severe DOC patients, following post-anoxic or traumatic brain injury and …20 healthy individuals (HC) as control group. Baseline electrophysiological evaluation evidenced, in comparison to HC, a partial preservation of cortical effective connectivity and excitability in clinically defined MCS, whereas these components were absent in clinically defined UWS. Then, we applied an anodal transcranial direct current stimulation (a-tDCS) protocol over the orbitofrontal cortex. Result: a-tDCS was able to boost cortical connectivity and excitability in all HC, MCS, and to unmask such excitability/connectivity in some UWS patients. Conclusion: a-tDCS could be useful in identifying residual connectivity markers in clinically-defined UWS, who may lack of purposeful behavior as a result of a motor-output failure. Show more

Keywords: Disorders of consciousness, minimally conscious state, unresponsive wakefulness syndrome, transcranial direct current stimulation, transcranial magnetic stimulation, cortical excitability, cortical connectivity

DOI: 10.3233/RNN-140448

Citation: Restorative Neurology and Neuroscience, vol. 33, no. 2, pp. 159-176, 2015

Authors: Caliandro, Pietro | Serrao, Mariano | Padua, Luca | Silvestri, Gabriella | Iacovelli, Chiara | Simbolotti, Chiara | Mari, Silvia | Reale, Giuseppe | Casali, Carlo | Rossini, Paolo M.

Article Type: Research Article

Abstract: Purpose: To investigate whether prefrontal cortex (PFC) functioning during ataxic gait is linked to compensatory mechanisms or to the typical intra-subject variability of the ataxic gait. Methods: Nineteen patients with chronic ataxia and fifteen healthy subjects were evaluated. The subjects were requested to walk along a straight distance of 10 meters while PFC oxygenation and gait parameters were assessed. PFC activity was evaluated by NIRO-200 while gait analysis was performed by the SMART-D500. To investigate the intra-subject variability of gait, we calculated the coefficient of multiple correlation (CMC) of the hip, knee and ankle kinematic waveforms furthermore, we evaluated the …step width. Results: We observed a positive correlation between PFC bilateral oxygenation changes and the step width (r = 0.54; p = 0.02 for the right PFC, and r = 0.50; p = 0.03 for the left PFC). No correlation was found between PFC activity and CMC of the hip, knee and ankle waveforms. Conclusions: Our results suggest that PFC activity is linked to gait compensatory mechanisms more than to the variability of the joint kinematic parameters caused by a defective cerebellar control. Show more

Keywords: Prefrontal cortex, ataxia, gait, balance, near-infrared spectroscopy, NIRS

DOI: 10.3233/RNN-140449

Citation: Restorative Neurology and Neuroscience, vol. 33, no. 2, pp. 177-187, 2015

Authors: Deng-Bryant, Ying | Readnower, Ryan D. | Leung, Lai Yee | Cunningham, Tracy L. | Shear, Deborah A. | Tortella, Frank C.

Article Type: Research Article

Abstract: Purpose: The present work compared the behavioral outcomes of ACCS therapy delivered either intravenously (i.v.) or intracerebroventricularly (i.c.v.) after penetrating ballistic-like brain injury (PBBI). Histological markers for neuroinflammation and neurodegeneration were employed to investigate the potential therapeutic mechanism of ACCS. Methods: Experiment-1, ACCS was administered either i.v. or i.c.v. for 1 week post-PBBI. Outcome metrics included behavioral (rotarod and Morris water maze) and gross morphological assessments. Experiment-2, rats received ACCS i.c.v for either 1 or 2 weeks post-PBBI. The inflammatory response was determined by immunohistochemistry for neutrophils and microglia reactivity. Neurodegeneration was visualized using silver staining. Results: Both i.v. and …i.c.v. delivery of ACCS improved motor outcome but failed to improve cognitive outcome or tissue sparing. Importantly, only i.c.v. ACCS treatment produced persistent motor improvements at a later endpoint. The i.c.v. ACCS treatment significantly reduced PBBI-induced increase in myeloperoxidase (MPO) and ionized calcium binding adaptor molecule 1 (Iba1) expression. Concomitant reduction of both Iba1 and silver staining were detected in corpus callosum with i.c.v. ACCS treatment. Conclusions: ACCS, as a treatment for TBI, showed promise with regard to functional (motor) recovery and demonstrated strong capability to modulate neuroinflammatory responses that may underline functional recovery. However, the majority of beneficial effects appear restricted to the i.c.v. route of ACCS delivery, which warrants future studies examining delivery routes (e.g. intranasal delivery) which are more clinically viable for the treatment of TBI. Show more

Keywords: Amnion-derived cellular cytokine solution, penetrating ballistic-like brain injury, rotarod, morris water maze, neuroinflammation, microglia, neutrophil, neurodegeneration

DOI: 10.3233/RNN-140455

Citation: Restorative Neurology and Neuroscience, vol. 33, no. 2, pp. 189-203, 2015

Authors: Liu, Yuanyuan | Yan, Hua | Chen, Song | Sabel, Bernhard A.

Article Type: Research Article

Abstract: Purpose: Vision loss after traumatic optic nerve injury is considered irreversible because of the retrograde loss of retinal ganglion cells (RGCs) which undergo apoptosis. Because the second messenger caspase-3 plays a major role in apoptosis, we now evaluated the efficacy of the specific caspase-3 inhibitor, Z-DEVD-FMK, in a rabbit model of fluid percussion injury (FPI) which mimics traumatic optic nerve injury in humans to enhance cell survival and improve vision. Methods: Survival of RGCs and recovery of vision were studied using retinal morphological markers and visual evoked potentials (VEP), respectively. The FPI traumatized animals were treated in their right eye …with a single intravitreal or peribulbar injection of Z-DEVD-FMK 30 min post-injury compared to 2% DMSO control injections in their left eye. Results: Intravitreal Z-DEVD-FMK, but not control injections, led to down-regulation of capase-3 and reduced, in a dose-dependent manner, RGCs apoptosis from 7 to 21 days post-injury. These morphological improvements were accompanied by vision restoration as documented by VEP. The neuroprotection after intravitreal injection of Z-DEVD-FMK was more effective than the peribulbar application. Conclusions: The caspase-3 inhibitor Z-DEVD-FMK is neuroprotective by inhibiting RGCs apoptosis when injected 30 min after optic nerve damage and significantly promotes restoration of vision. A controlled clinical trial is now needed to evaluate the efficacy and safety of Z-DEVD-FMK in humans. Show more

Keywords: Caspase-3 inhibitor, optic nerve injury, apoptosis, neuroprotection, vision restoration

DOI: 10.3233/RNN-159001

Citation: Restorative Neurology and Neuroscience, vol. 33, no. 2, pp. 205-220, 2015

Authors: Freundlieb, Nils | Philipp, Stephan | Drabik, Anna | Gerloff, Christian | Forkert, Nils D. | Hummel, Friedhelm C.

Article Type: Research Article

Abstract: Purpose: Transcranial magnetic stimulation (TMS) and measurements of upper limb function were longitudinally applied to gain further insights into processes involved in functional recovery from the acute to the chronic stage after stroke. Methods: 10 acute stroke patients were monitored over 6 months behaviourally and with established TMS protocols. By using neuronavigated motor mapping, behavioural parameters, and a mixed model analysis, the role of the frontal and parietal part of the motor area of both hemispheres for functional recovery was determined. Results: Size and volume of the ipsilesional motor area (MAipsi ) were significantly decreased in the acute phase compared …to the contralesional motor area (MAcontra ). Size of MAipsi , especially its frontal part, changed over time and was positively correlated with functional recovery, whereas resting motor threshold, volume of both MA or the shift of its center of gravity did not show any association with recovery. Conclusion: The present data suggests the presence of a positive correlation between changes of the motor representation of the lesioned hemisphere and functional recovery after stroke. A possible interpretation is that rather (re-)activated corticomotor outputs are substrates of functional recovery after stroke than increased efficacy of residual, non-lesioned pathways. Show more

Keywords: Neuronavigation, transcranial magnetic stimulation, stroke, motor recovery, plasticity

DOI: 10.3233/RNN-140454

Citation: Restorative Neurology and Neuroscience, vol. 33, no. 2, pp. 221-231, 2015

Authors: Manthou, M. | Nohroudi, K. | Moscarino, S. | Rehberg, F. | Stein, G. | Jansen, R. | Abdulla, D. | Jaminet, P. | Semler, O. | Schoenau, E. | Angelov, D.N.

Article Type: Research Article

Abstract: Purpose: Based on several positive effects of whole-body-vibration (WBV) therapy on recovery after SCI, we looked for correlations between functional (analysis of locomotion), electrophysiological (H-reflex) and morphological (density of functioning capillaries) measurements after SCI and WBV-treatment. Methods: Severe compression SCI at low-thoracic level (T8) in adult female Wistar rats was followed by WBV twice a day (2 × WBV) over a 12-week post-injury period. Intact rats and rats with SCI but no WBV-therapy (“No-WBV”) served as controls. Recovery of locomotion was determined by BBB-locomotor rating, foot stepping angle (FSA), rump-height index (RHI), correct ladder steps (CLS) and H-reflex at 1, …3, 6, 9, and 12 weeks after SCI. Animals were sacrificed by an overdose of Isoflurane (Abbott). One hour later their spinal cords were fixed in 4% PFA for 24 h. Samples from the thoracic cord containing the lesion site and from the lumbar intumescence were cut into 10 μm thick longitudinal frozen sections. Results: All functioning capillaries were unequivocally identified because the endogenous peroxidase of the erythrocytes was clearly visualized with 0.05% diaminobenzidine (DAB). A determination of their absolute (in μm2 ) and proportional areas (percent of photographed tissue) revealed a significantly denser capillary network in the WBV-treated rats: 1,66 ± 0,41% in the “vibrated” rats versus 0,79 ± 0,19% in the “No-WBV” animals. The portion of the capillary network in intact rats was 1,51 ± 0,69%. Surprisingly, even though the vascularization in the treated animals was significantly increased, this had no beneficial influence on the recovery of functions after SCI. Conclusion: The results of this study provide for the first time evidence that intensive WBV-therapy leads to a significantly denser capillary network in the lesioned spinal cord. However, since this higher capillary density is not associated with improved functional recovery (possibly because it exceeded the balance necessary for functional improvements), optional treatments with lower intensity or less time of WBV-therapy should be tested. Show more

Keywords: Spinal cord injury, rehabilitation, whole body vibration, functional parameters, morphological changes, angiogenesis, revascularization, functional recovery, DAB

DOI: 10.3233/RNN-140434

Citation: Restorative Neurology and Neuroscience, vol. 33, no. 2, pp. 233-249, 2015