Restorative Neurology and Neuroscience - Volume 31, issue 5

Authors: Feeney, Erin J. | Stephenson, Diane | Kleiman, Robin | Bove, Susan | Cron, Courtney | Moody, Lara | Robinson, Mercedes | Ramirez, Julio J.

Article Type: Research Article

Abstract: Purpose: Transgenic manipulation of mouse physiology facilitates the preclinical study of genetic risk factors, neural plasticity, and reactive processes accompanying Alzheimer's disease. Alternatively, entorhinal cortex lesions (ECLs) model pathophysiological denervation and axonal sprouting in rat. Given reports of anatomical differences between the mouse and rat hippocampus, application of the ECL paradigm to transgenic mice first requires comprehensive characterization of axonal sprouting in the wild-type. Methods: Adult male C57BL/6 mice sustained unilateral transections of the perforant pathway. Subjects were sacrificed at 1, 4, 10, 18, and 28 days postlesion, and hippocampal sections were stained for AChE, the postsynaptic terminal marker drebrin, …and the presynaptic terminal proteins SNAP-25, GAP-43, synapsin, and synaptophysin. To examine synaptic turnover and reinnervation, ipsilateral-to-contralateral staining densities were determined within the dentate molecular layer, and shrinkage-corrected ratios were compared to 28 day-yoked sham cases. Results: At 28 days postlesion, ipsilateral terminal marker densities exhibited significant depression. In contrast, qualitative analyses at earlier time points suggested altered AChE staining patterns and increased SNAP-25 and synapsin immunoreactivity in the inner molecular layer (IML) of the dentate gyrus. Conclusions: C57BL/6 mice exhibit synaptic reorganization following perforant path transections. The IML may provide a key target for evaluation and intervention in ECL mouse models. Show more

Keywords: Reactive sprouting, C57BL/6, AChE, drebrin, GAP-43, SNAP-25, synapsin, synaptophysin, entorhinal cortex, hippocampus

DOI: 10.3233/RNN-130311

Citation: Restorative Neurology and Neuroscience, vol. 31, no. 5, pp. 517-531, 2013

Authors: Kimberley, Teresa Jacobson | Borich, Michael R. | Arora, Sanjeev | Siebner, Hartwig R.

Article Type: Research Article

Abstract: Purpose: The ability of low-frequency repetitive transcranial magnetic stimulation (rTMS) to enhance intracortical inhibition has motivated its use as a potential therapeutic intervention in focal hand dystonia (FHD). In this preliminary investigation, we assessed the physiologic and behavioral effects of multiple sessions of rTMS in FHD. Methods: 12 patients with FHD underwent five daily-sessions of 1 Hz rTMS to contralateral dorsal premotor cortex (dPMC). Patients held a pencil and made movements that did not elicit dystonic symptoms during rTMS. We hypothesized that an active but non-dystonic motor state would increase beneficial effects of rTMS. Five additional patients received sham-rTMS protocol. …The area under curve (AUC) of the motor evoked potentials and the cortical silent period (CSP) were measured to assess changes in corticospinal excitability and intracortical inhibition, respectively. Behavioral measures included pen force and velocity during handwriting and subjective report. Results: Multiple-session rTMS strengthened intracortical inhibition causing a prolongation of CSP after 3 days of intervention and pen force was reduced at day 1 and 5, leaving other measures unchanged. 68% of patients self-reported as ‘responders’ at day 5, and 58% at follow-up. Age predicted responders. Conclusions: A strong therapeutic potential of this rTMS paradigm in FHD was not supported but findings warrant further investigation. Show more

Keywords: Focal hand dystonia, rehabilitation, rTMS, writer's cramp, clinical

DOI: 10.3233/RNN-120259

Citation: Restorative Neurology and Neuroscience, vol. 31, no. 5, pp. 533-542, 2013

Authors: Qinli, Zhang | Meiqing, Li | Xia, Jiao | Li, Xu | Weili, Guo | Xiuliang, Ji | Junwei, Ji | Hailan, Yang | Ce, Zhang | Qiao, Niu

Article Type: Research Article

Abstract: Purpose: There are many in vivo and in vitro studies suggested the involvement of apoptosis in neurodegenerative processes. There is considerable evidence that various complex events may contribute to neural cell death. The present study focuses on the underlined neurodegenerative mechanism and the preventive effect of necrostatin-1 (Nec-1) on neural cell death induced by aluminum (Al). Methods: Al-exposed primary cultures of newborn mice cortical cells were separately treated with 3-methylamphetamine (3-MA), benzyloxycarbonylvalyl-alanyl–aspartic acid (O-methyl)–fluoro-methylketone (zVAD-fmk), and Nec-1, the cell viability analysis was used to evaluate cell damage from apoptosis, necroptosis and autophagy. Morphology of neural cells treated with 2 mM …Al, and 2 mM Al plus 60 μM Nec-1 were examined by fluorescent microscope, and the cell death rates were quantified by cytometry. For the in vivo experiments, male ICR mice were microinjected with normal saline, 2 mM Al, and 2 mM Al plus Nec-1 at the concentrations of 2 mM, 4 mM and 8 mM into the lateral cerebral ventricles. The Morris water maze task was performed in 20 days after intracerebroventricular injection, Nissl staining was used to demonstrate the loss of Nissl substance and the number of neural cells, and western blot was used to analyze the expressing of cell death and Alzheimer's disease related proteins. Results: The cell viabilities inhibited by Al could be enhanced by 3-MA, zVAD-fmk and Nec-1, of which Nec-1 improved the cell viability most significantly. Furthermore, the cell viability of neural cells treated with Nec-1 increased concentration-dependently, and the expressions of cell death-related proteins were decreased also in a concentration-dependent manner. The in vivo experiments indicated that administration of Nec-1 on Al-treated mice significantly improved learning and memory retention in the Morris water maze task, decreased the neural cells death and inhibited the expression of Alzheimer's disease related proteins in the mice brain. Conclusions: The present study provides the first direct evidence of a connection between necroptosis and neurodegeneration, which indicates that necroptosis is involved in neurodegenerative cell death. Furthermore, Nec-1 may be useful for the prevention and treatment of neurodegenerative disorders. Show more

Keywords: Necrostatin-1, necroptosis, neurodegeneration, cell death, aluminum

DOI: 10.3233/RNN-120304

Citation: Restorative Neurology and Neuroscience, vol. 31, no. 5, pp. 543-555, 2013

Authors: Ernst, Jennifer | Grundey, Jessica | Hewitt, Manuel | von Lewinski, Friederike | Kaus, Jürgen | Schmalz, Thomas | Rohde, Veit | Liebetanz, David

Article Type: Research Article

Abstract: Purpose: Functional electrical stimulation represents an alternative to conventional and passive ankle foot orthosis (AFO) for the treatment of stroke-related drop foot. We evaluated the implantable 4-channel stimulator ActiGait, which selectively and directly stimulates the peroneal nerve. In addition, it bypasses the need for surface electrodes and cables. Methods: Walking speed (10-meter gait test, [m/s]) and walking endurance (6-minute gait test [m/6min]) of 5 patients were tested prior to, as well as 6 and 12 weeks after, the implantation of the ActiGait implantable drop foot stimulator system. In addition, ankle joint angles were assessed during specific phases of the gait …cycle, i.e. initiation angle (IA) at the first contact of the foot to the floor, initial plantar flexion (IPF), dorsiflexion (DF) and final plantar flexion (FPF) in [°] during stance phase. The ankle joint angles were measured at baseline and 12 weeks after ActiGait implantation. Results: At the first follow-up, patients' gait speed was found to have increased (0.55; 0.77 m/s) as had walking endurance (211; 260 m). Improvement in gait speed (0.55; 0.77 m/s) and endurance (214; 248 m) was still present after 12 weeks. In addition, gait analysis after 12 weeks revealed a nearly normal physiological initiation angle (113° vs 122°) and an increase in the initial plantar flexion (7° vs. 0°). The initiation angle (IA) represents a well-suited parameter for adequate pre-positioning of the foot at the beginning of the stance phase and is necessary to prevent stumbling and falling. Furthermore, IA is identical to the maximum achieved dorsiflexion during the swing phase of gait. Thus, analysis of the IA of subjects walking with the implantable drop foot stimulator systems ActiGait is particularly useful in showing that the implantable system restores the IA towards physiological ankle movements. Conclusion: The ActiGait system increased gait speed, walking endurance and the physiology of important ankle joint kinematics. This is most likely a result of ankle dorsiflexion by active peroneal stimulation during the swing phase of gait and optimized prepositioning (IA) of the foot at the beginning of stance phase. The ActiGait system represents a therapeutic option for the treatment of patients suffering drop foot due to a cerebrovascular insult. Show more

Keywords: Drop foot, functional electrical stimulation, neurostimulation, peroneal nerve, rehabilitation, stroke, gait

DOI: 10.3233/RNN-120283

Citation: Restorative Neurology and Neuroscience, vol. 31, no. 5, pp. 557-569, 2013

Authors: Anastassiou, Gerasimos | Schneegans, Anna-Lena | Selbach, Michael | Kremmer, Stephan

Article Type: Research Article

Abstract: Purpose: To evaluate the effect of transpalpebral electrotherapy on patients with dry age-related macular degeneration (AMD). Methods: 22 patients were randomized in two groups to either receive therapy (n = 12) or placebo (n = 10). There was no statistically significant difference for age and initial visual acuity (VA) between the two groups (p = 0.6; ANOVA). Treatment was performed on 5 consecutive days. On each day two sessions were applied. Every session included 8 spots (40 sec/spot) around the eye globe. The current applied (changing frequency 5–80 Hz) varied individually between 150 and 220 μA. Patients were examined before …treatment, at the end of the 5-day treatment period, after 4 weeks and at 6 months. Examinations included a standardized VA testing, using ETDRS letters, contrast sensitivity, macular sensitivity and fixation stability using microperimetry and measurements with SD-OCT. Results: At the end of week 1, mean VA improved markedly (p = 0.001; T test), with 7 out of 12 patients showing an improvement of more than 5 letters. After 4 weeks, there was an improvement of more than 10 letters in 3 patients (mean + 5.7 letters; p = 0.001; T test) whereas at 6 months a loss of 1.6 letters was observed. Only 4 (33%) of our patients did not show any improvement at all. Contrast sensitivity displayed a similar pattern. Within one week after treatment, there was a rapid improvement (+4.4 optotypes; p = 0.006; T test). After 6 months, contrast sensitivity declined again (+1.5 optotypes; p = 0.2; T test). Compared to the placebo group changes on VA failed statistical significance (p = 0.1 at 4 week; T test) whereas changes on contrast sensitivity were statistically significant (p = 0.01 at week 4; T test). No adverse events were seen or reported during the study period. Conclusions: To the best of our knowledge, this is the first report of a transpalpebral electrostimulation in patients with dry AMD that demonstrates a temporary increase in visual function in some of these patients; results that seem to justify further research on this potential treatment option for dry AMD. Show more

Keywords: AMD, electrical stimulation, therapy, choroid, electrostimulation, transpalpebral

DOI: 10.3233/RNN-130322

Citation: Restorative Neurology and Neuroscience, vol. 31, no. 5, pp. 571-578, 2013

Authors: Lopez, William Omar Contreras | Nikkhah, Guido | Kahlert, Ulf D. | Maciaczyk, Donata | Bogiel, Tomasz | Moellers, Sven | Schültke, Elisabeth | Döbrössy, Máté | Maciaczyk, Jaroslaw

Article Type: Research Article

Abstract: Purpose: The concept of transplantation of neuronal cells to treat Huntington's and Parkinson's diseases is based on the proven principle that dopaminergic and GABA-ergic progenitor neurons (from the human developing ventral mesencephalon and whole ganglionic eminence) can survive, differentiate and functionally integrate into an allogenic host brain. However, several donor and host-specific variables play a major role in the safety and outcome of this procedure. In this paper, we seek to summarize an updated neural transplantation protocol, based on our institutional experience and many years of collaboration with other neurotransplantation centers. Methods: We present a detailed clinical neurotransplantation protocol for …Parkinson's (PD) and Huntington's (HD) diseases with special emphasis in understanding the anatomical relationships of the human fetal tissue that are relevant for selection of the desired cell populations. Results: Two detailed step-wise neurotransplantation protocols are presented, outlining strategies facilitating the avoidance of possible procedure-related complications. Conclusions: In this paper we delineated some crucial technical factors enabling the execution of a safe and effective neural transplantation. The protocols presented here might contribute to further development of the experimental clinical neurotransplantation towards a routine therapeutic procedure. Show more

Keywords: Human fetal neural precursor cells (hFNPCs), neural stem cells (NSC), neural transplantation, ventral mesencephalon (VM), whole ganglionic eminence (WGE), substantia nigra (SN), Parkinson's disease (PD), Huntington's disease (HD), good clinical practice (GCP)

DOI: 10.3233/RNN-130317

Citation: Restorative Neurology and Neuroscience, vol. 31, no. 5, pp. 579-595, 2013

Authors: Su, Caixin | Zhang, Donald | Truong, John | Jiang, Cai | Lee, Sam | Jarouche, Mariam | Hennell, James R. | Rathbone, Michel P. | Sucher, Nikolaus J. | Jiang, Shucui

Article Type: Research Article

Abstract: Purpose: Acute spinal cord injury (SCI) triggers multiple cellular and molecular pathways; therapy aimed at only one pathway is unlikely to succeed. Anecdotal reports indicate that a novel herbal formulation (JSK—Ji-Sui-Kang) may enhance recovery in humans with SCI. We investigated whether JSK's therapeutic effects could be verified in a well-established SCI model in rats. Methods: Therapeutic effects of JSK were tested using a standard behavioral assessment, histological, immunochemical and microarray analysis. Phytochemical fingerprinting of JSK was performed using high performance liquid chromatography coupled with photodiode array detection and electrospray ionization-mass spectrometry. JSK or vehicle was gavaged to rats 24 hours …after SCI and daily thereafter for 3 weeks. Results: Locomotor function significantly improved (n = 12; p < 0.05), tissue damage was reduced (p < 0.01; n = 6) and more axons and myelin were observed in JSK-treated compared with vehicle control animals. JSK significantly enhanced expression of neuroglobin, vascular endothelial growth factor and growth-associated protein 43, and reduced the expression of caspase 3, cyclooxygenase-2, RhoA (p < 0.05; n = 6) and fibrinogen (p < 0.01; n = 6). RNA microarray indicated that JSK altered transcription of genes involved in ischemic and inflammatory/immune responses and apoptosis (p < 0.05; n = 3). Conclusions: JSK appears to target multiple biochemical and cellular pathways to enhance functional recovery and improve outcomes of SCI. The results provide a basis for further investigation of JSK's effects following SCI. Show more

Keywords: Inflammation, apoptosis, herbal formula, spinal cord injury, immunohistochemistry, Phytochemical fingerprinting

DOI: 10.3233/RNN-120303

Citation: Restorative Neurology and Neuroscience, vol. 31, no. 5, pp. 597-617, 2013

Authors: Scarpazza, C. | Braghittoni, D. | Casale, B. | Malagú, S. | Mattioli, F. | di Pellegrino, G. | Ladavas, E.

Article Type: Research Article

Abstract: Purpose: Although neuropsychological impairments are common in Multiple Sclerosis (MS), the manifestation of cognitive deficits may vary greatly across MS patients. Here, we explored the influence of cognitive reserve proxy indices (education and occupation) and perceived fatigue on cognitive performance. Methods: Fifty relapsing-remitting MS patients were evaluated. Cognitive performance was measured using the Paced Auditory Serial Addition Test (PASAT), in which information processing speed can be manipulated by varying the presentation speed of stimuli. Results: MS patients with low education performed worse than healthy controls at faster PASAT speeds. By contrast, no difference was observed between MS patients with high …education and matched healthy controls, regardless of PASAT speed. Moreover, we found that neither occupational attainment nor perceived fatigue has an influence on MS patients' cognitive performance. Conclusion: These findings provide evidence that higher education could be protective against MS-associated cognitive deficits and that high speed PASAT versions are more suitable for identifying compensatory capacities compared to low speed PASAT versions. Show more

Keywords: Multiple sclerosis, education, cognitive reserve

DOI: 10.3233/RNN-120261

Citation: Restorative Neurology and Neuroscience, vol. 31, no. 5, pp. 619-631, 2013

Authors: Manella, Kathleen J. | Field-Fote, Edelle C.

Article Type: Research Article

Abstract: Purpose: Sparse data exist about effects of locomotor training on spasticity in individuals with spinal cord injury (SCI). We investigated changes in spastic responses in individuals with motor-incomplete SCI (MISCI) associated with locomotor training and examined properties of a biomechanical measure of clonus severity, plantar flexor reflex threshold angle (PF RTA). Methods: In 18 individuals with chronic MISCI, we assessed biomechanical and electrophysiologic measures of extensor spasticity and their relationship with walking speed before and after 12 weeks of body-weight supported locomotor training. Measures included PF RTA, plantar flexor (ankle clonus) and quadriceps spasm duration, soleus H-reflex, and ankle muscle …electromyography. PF RTA validity was assessed by measuring PF RTA and clonus duration in 40 individuals with SCI and 10 non-disabled individuals. Results: Locomotor training was associated with decreased PF RTA (p = 0.06), ankle clonus (p = 0.09) and quadriceps spasm (p = 0.05). PF RTA discriminated between non-disabled individuals and individuals with SCI and was moderately correlated with walking speed, soleus H/M ratio, and quadriceps spasm duration. Conclusions: In persons with spastic paresis due to MISCI, locomotor training was associated with decreased spasticity as measured by decreased plantar flexor excitability, ankle clonus, and quadriceps spasm. Show more

Keywords: Ankle clonus, plantar flexor hyperreflexia, quadriceps spasm, measurement

DOI: 10.3233/RNN-120255

Citation: Restorative Neurology and Neuroscience, vol. 31, no. 5, pp. 633-646, 2013

Authors: Wang, Tao | Van, Ken C. | Gavitt, Brian J. | Grayson, J. Kevin | Lu, Yi-Cheng | Lyeth, Bruce G. | Pichakron, Kullada O.

Article Type: Research Article

Abstract: Purpose: Repetitive mild traumatic brain injury (TBI) is a major military and sports health concern. The purpose of this study was to determine if a diet rich in omega-3 fatty acids would reduce cognitive deficits and neuronal cell death in a novel fluid percussion rat model of repetitive mild TBIs. Methods: Thirty-two Sprague-Dawley rats were assigned to either an experimental rat chow enhanced with 6% fish oil (source of omega-3 fatty acids) or a control rat chow. Both rat chows contained equivalent quantities of calories, oil, and nutrients. After four weeks, both groups received mild repetitive bilateral fluid percussion TBIs …on two sequential days. Pre-injury diets were resumed, and the animals were monitored for two weeks. On post-injury days 10–14, Morris Water Maze testing was performed to assess spatial learning and cognitive function. Animals were euthanized at 14 days post-injury to obtain specimens for neurohistopathology. Results: There was no difference in pre-injury weight gain between groups. Post-injury, animals on the fish oil diet lost less weight and recovered their weight significantly faster. By 14 days, the fish oil diet group performed significantly better in the Morris Water Maze. Neurohistopathology identified a non-significant trend toward a higher density of hippocampal neurons in the fish oil diet group. Conclusions: Pre-injury dietary supplementation with fish oil improves recovery of body weight and provides a small improvement in cognitive performance in a rat model of multiple mild TBIs. Show more

Keywords: Mild traumatic brain injury, omega-3 fatty acids, dietary supplementation, hippocampus, morris water maze

DOI: 10.3233/RNN-130316

Citation: Restorative Neurology and Neuroscience, vol. 31, no. 5, pp. 647-659, 2013