Restorative Neurology and Neuroscience - Volume 25, issue 2

Authors: Keck, Carrie A. | Thompson, Hilaire J. | Pitkänen, Asla | LeBold, David G. | Morales, Diego M. | Plevy, Jamie B. | Puri, Rishi | Zhao, Boyu | Dichter, Marc | McIntosh, Tracy K.

Article Type: Research Article

Abstract: Purpose: To evaluate the therapeutic efficacy of two antiepileptic compounds, RWJ-333369 and RWJ-333369-A in a well-established experimental model of lateral fluid percussion (FP) traumatic brain injury (TBI) in the rat. Methods: Anethestized Male Sprague-Dawley rats (n=227) were subjected to lateral FP brain injury or sham-injury. Animals were randomized to receive treatment with RWJ-333369 (60 mg/kg, p.o.) or its analog RWJ-333369-A (60 mg/kg, p.o.), or vehicle (equal volume) at 15 minutes, 4, 8, and 24 hours …post-injury. In Study I, animals were assessed at 48 hours for acute motor and cognitive function and then sacrificed to evaluate regional cerebral edema. In Study II, animals were evaluated post-injury for motor function at 48 hours and weekly thereafter from 1 to 4 weeks. Post-traumatic learning ability was assessed 4 weeks post-injury, followed by evaluation of hemispheric tissue loss. Results: In Study I, no improvement in acute memory or motor function was observed following administration of either RWJ-333369 or RWJ-333369-A in brain-injured animals compared to vehicle-treated, brain-injured animals. However, brain-injured animals receiving treatment with RWJ-333369-A had a significant reduction in post-traumatic cerebral edema in both injured and contralateral hippocampus compared to brain-injured, vehicle-treated controls (p<0.05). In Study II, treatment with either compound did not result in any improvement of neuromotor function, learning ability or change in lesion volume following brain injury. Show more

Citation: Restorative Neurology and Neuroscience, vol. 25, no. 2, pp. 77-90, 2007

Authors: Miklyaeva, Elena I. | Whishaw, Ian Q. | Kolb, Bryan

Article Type: Research Article

Abstract: Purpose: Unilateral dopamine (DA) depletion in the rat provides an analog of human Parkinson's disease. The classic view of DA loss is that it produces changes in the activity of striatal-cortical circuitry that results in reduced frontal cortex neural activity. This "functional deafferent" view is consistent with findings that animals display sensorimotor deficits in the contralateral-to-lesion side of the body and compensatory behavior adjustments in the ipsilateral-to-lesion side of the body. The present study examined how …DA depletion and the associated sensorimotor changes affect the morphology of the ipsilateral or contralateral neocortex neurons as assessed by dendritic morphology in Golgi-stained tissue. Method: Rats were given unilateral 6-hydroxydopamine (6-OHDA) or sham lesions in the nigrostriatal bundle. Lesion success was confirmed by enduring bilateral motor impairments in a skilled-reaching task, compensatory use of the ipsilateral-to-lesion limbs, and by increases in amphetamine and apomorphine-induced rotational behavior. Results: Brains processed for Golgi-Cox staining at 1, 3, 8, or 24 months after the lesion showed no changes in dendritic arborization or synapse number in layer V pyramidal cells of motor cortex ipsilateral to the 6-OHDA lesion (DA-depleted hemisphere) at any postsurgical recovery stage. There was an increase in dendritic arborization in all lesion groups in the hemisphere contralateral to the lesion (good hemisphere). Conclusion: The results are inconsistent with the classical view of frontal cortex functional deafferentiation due to DA loss but do suggest that compensatory behavior leads to dendritic hypertrophy in the good hemisphere. Show more

Keywords: Dendritic arborization and dopamine, dopamine and cortical neurons, dopamine depletion, Golgi and dopamine, 6-OHDA lesion, nigrostriatal bundle lesion, Parkinson rat, skilled reaching, spine density, dopamine

Citation: Restorative Neurology and Neuroscience, vol. 25, no. 2, pp. 91-99, 2007

Authors: Peurala, Sinikka H. | Könönen, Paavo | Pitkänen, Kauko | Sivenius, Juhani | Tarkka, Ina M.

Article Type: Research Article

Abstract: Purpose: It is known that visuospatial orientation and the extent of spontaneous recovery vary between right or left hemisphere affected stroke patients. We hypothesized that the right hemisphere affected chronic patients would show more impaired static balance than left hemisphere affected patients. The purpose of the study was to assess displacement of the center of pressure (COP) of ambulatory patients with either left or right hemiparesis. Methods: Forty-five patients and thirty healthy subjects participated and …static balance was measured while standing on a force plate. Results: The patients showed more than four times higher mean velocity moment and two times faster anterior-posterior (AP) and medial-lateral (ML) speed of COP displacement than healthy subjects. The patients with left hemiparesis, and affected right hemisphere, had higher power peak magnitudes of COP displacements than patients with right hemiparesis both in ML and AP directions at low frequencies. The patients had higher power peak magnitudes of COP displacements than healthy subjects in both ML and AP directions at all separately analyzed frequency ranges. More weight bearing on the paretic side was associated with less COP displacement in ML and AP directions. Conclusions: Patients with left hemiparesis have more low frequency COP movements from side to side and from front to back than patients with right hemiparesis. Patients with right or left hemiparesis sway more than the healthy subjects. The affected hemisphere and the disturbed cerebral networks likely produce different postural deficits in right or left hemiparetic patients. Show more

Keywords: Balance, cerebrovascular disorders, hemiparesis, posture

Citation: Restorative Neurology and Neuroscience, vol. 25, no. 2, pp. 101-108, 2007

Authors: Watanabe, Kota | Nakamura, Masaya | Okano, Hideyuki | Toyama, Yoshiaki

Article Type: Research Article

Abstract: Purpose: Recent studies demonstrated that transplanting neural stem/precursor cells (NSPCs) into an injured spinal cord of adult rat promotes functional recovery. The functional recovery from spinal cord injury might be enhanced by transplanting NSPCs with a scaffold that fills the cavity, entraps the NSPCs in the cavity, and acts as an attachment for neurite extension. We recently focused on collagen type-1 as a scaffold for NSPC transplantation into the injured spinal cord. In the present study, …we determined the optimal conditions for culturing NSPCs in 3D collagen type-1 gel with respect to cell survival and cell migration. We, then, evaluated the ability of NSPCs to differentiate under the optimal condition. Methods: NSPCs were derived from the striatum of rat embryos. To determine the optimal cell density and collagen concentration for 3D collagen gel culture for NSPC, we performed viability assay and migration assay. Then, we examined the proportion of phenotypes differentiated from NSPC in that optimal condition. Results: In viability assay, the viability rate increased as the NSPC density increased, and peaked at 1 × 10^{7} to 5 × 10^{7} cell/ml. For collagen concentration, the viability rate increased as the collagen concentration decreased. In migration assay, cell migration was most extensive at collagen concentrations between 0.3 and 0.75 mg/ml. Migration distances gradually declined as collagen concentrations increased. In the optimal condition, NSPCs differentiated into neurons (40.1%), astrocytes (53.1%), and oligodendrocytes (5.3%) in 3D collagen gel culture. Conclusion: The optimal conditions for NSPC culture in 3D collagen gel was a cell density between 1 × 10^{7} and 5 × 10^{7} cells/ml and a collagen concentration between 0.5 and 0.75 mg/ml. Under the condition, NSPCs could differentiate into neurons, astrocytes, and oligodendrocytes. Show more

Keywords: Collagen type-1, three-dimensional culture, neural stem precursor cell, scaffold

Citation: Restorative Neurology and Neuroscience, vol. 25, no. 2, pp. 109-117, 2007

Authors: van Kesteren, Marlieke T.R. | Wiersinga-Post, J. Esther C.

Article Type: Research Article

Abstract: Purpose: Several studies on auditory temporal-order processing showed gender differences. Women needed longer inter-stimulus intervals than men when indicating the temporal order of two clicks presented to the left and right ear. In this study, we examined whether we could reproduce these results in order to further investigate the differences in auditory processing between men and women. Methods: Neurologically healthy subjects (13 males and 13 females, age range: 19 to 37 years) had to …identify the temporal order of two clicks, presented monaurally to the left and right ear. Thresholds for the inter-stimulus intervals between the clicks were determined using a three step transformed up-down procedure. Results: The results show no influence of gender in the auditory temporal-order task. Inter-individual differences were, however, large, ranging from a threshold of around 15 ms to around 90 ms. Conclusion: Contrary to what was found in previous studies, no significant gender difference was measured in temporal-processing abilities using a task with monaurally presented clicks. Show more

Keywords: Auditory-temporal processing, temporal-order threshold, sex difference, diagnostics

Citation: Restorative Neurology and Neuroscience, vol. 25, no. 2, pp. 119-122, 2007

Authors: Boggio, Paulo S. | Nunes, Alice | Rigonatti, Sergio P. | Nitsche, Michael A. | Pascual-Leone, Alvaro | Fregni, Felipe

Article Type: Research Article

Abstract: Purpose: Recent evidence has suggested that a simple technique of noninvasive brain stimulation – transcranial direct current stimulation (tDCS) – is associated with a significant motor function improvement in stroke patients. Methods: We tested the motor performance improvement in stroke patients following 4 weekly sessions of sham, anodal- and cathodal tDCS (experiment 1) and the effects of 5 consecutive daily sessions of cathodal tDCS (experiment 2). A blinded rater evaluated motor function using the …Jebsen-Taylor Hand Function Test. Results: There was a significant main effect of stimulation condition (p=0.009) in experiment 1. Furthermore there was a significant motor function improvement after either cathodal tDCS of the unaffected hemisphere (p=0.016) or anodal tDCS of the affected hemisphere (p=0.046) when compared to sham tDCS. There was no cumulative effect associated with weekly sessions of tDCS, however consecutive daily sessions of tDCS (experiment 2) were associated with a significant effect on time (p< 0.0001) that lasted for 2 weeks after treatment. Conclusions: The findings of our study support previous research showing that tDCS is significantly associated with motor function improvement in stroke patients; and support that consecutive daily sessions of tDCS might increase its behavioral effects. Because the technique of tDCS is simple, safe and non-expensive; our findings support further research on the use of this technique for the rehabilitation of patients with stroke. Show more

Keywords: Rehabilitation, transcranial direct current stimulation, brain DC polarization

Citation: Restorative Neurology and Neuroscience, vol. 25, no. 2, pp. 123-129, 2007

Authors: Sinis, Nektarios | Schaller, Hans-Eberhard | Becker, Stephan Thomas | Schlosshauer, Burkhard | Doser, Michael | Roesner, Harald | Oberhoffner, Sven | Müller, Hans-Werner | Haerle, Max

Article Type: Research Article

Abstract: Purpose: Recently we successfully used a conduit of ε-caprolactone-co-trimethylene carbonate filled with Schwann cells (SC) across a 20 mm gap in a rat median nerve. In this study we applied the tubes with SC across a 40 mm gap in order to analyse the regenerative potential of the tubes in long nerve defects. Methods: To augment the nerve defect a cross-chest procedure was used and the tubes were implanted with injected isogeneic SCs inside …(group 3). Both ulnar nerves were used for a 40 mm autograft (group 2). For control group non-operated animals were used (group 1). The grasping test, histology (S-100, PAM), electrophysiology, and the muscle weight were used to assess regeneration. Results: After 12 months, grasping was seen only in three animals of group 3 (3.6 g [95% CI: 0 to 7.6 g]). However, in group 2 all rats had a partial functional regeneration (42.8 g [95% CI: 39.1 to 46.6 g]). The grasping force of the non-operated animals (group 1) was 240.9 g [95% CI: 237.2 to 244.7 g] at the time. Histology from group 3 confirmed an irregular arrangement of fibres in contrast to more organized structures in group 2. Electrophysiology in group 3 displayed potentials only in the three animals with functional regeneration. In group 2 all animals exhibited potentials. A significant decrease of muscle weight was observed in groups 2 and 3, most prominent in the latter. Conclusion: Regeneration was not successful across the 40 mm gap using the applied tube in combination with SC. For future experiments further consideration should be taken in optimizing the cellular and material components that are critical for a successful application to overcome very large nerve gaps. Show more

Keywords: Schwann cells, nerve conduit, nerve regeneration, cross-chest procedure

Citation: Restorative Neurology and Neuroscience, vol. 25, no. 2, pp. 131-141, 2007

Authors: Restemeyer, C. | Weiller, C. | Liepert, J.

Article Type: Research Article

Abstract: Purpose: Drugs that modulate neuronal transmission can influence motor recovery after stroke. Here, we tested if a single dose of levodopa could improve motor functions and change motor excitability in a group of chronic stroke patients. Methods: Ten patients > 6 months after their stroke participated in a placebo-controlled double-blind trial. On two different occasions, they received either 100 mg levodopa or placebo in a randomized order. After drug intake, they participated in one …hour of physiotherapy aimed at an improvement of dexterity. Motor functions were tested by application of the Nine-Hole-Peg Test, a dynamometer measuring grip strength and the Action Research Arm Test. In addition, transcranial magnetic stimulation (TMS) was applied to study intracortical excitability, stimulus response curves and silent periods. TMS studies and motor function measurements were performed before drug intake, 45 minutes after drug ingestion and after the physiotherapy. Results: Compared to placebo, levodopa neither improved motor functions nor changed motor excitability as tested by TMS. Conclusion: These findings suggests that a single levodopa dose is not sufficient to improve motor function in chronic stroke. However, it cannot be excluded that the lack of a beneficial effect is related to the small study sample. Show more

Keywords: Stroke, rehabilitation, levodopa, motor function, transcranial magnetic stimulation

Citation: Restorative Neurology and Neuroscience, vol. 25, no. 2, pp. 143-150, 2007

Authors: Sayeed, Iqbal | Wali, Bushra | Stein, Donald G.

Article Type: Research Article

Abstract: Purpose: Previous studies suggest that progesterone (PROG) has a substantial protective effect against several types of brain injury. Since most cases of human stroke are caused by permanent occlusion of cerebral arteries, we assessed the neuroprotective effects of PROG on cerebral infarction and behavioral deficits in a permanent MCAO (pMCAO) model. Methods: pMCAO was produced by surgical insertion of a silicone-coated nylon filament into the right internal carotid artery. Laser-Doppler flowmetry was used to …monitor cerebral blood flow for 10 min post-occlusion. PROG (8 mg/kg) or vehicle (2-hydroxypropyl-β-cyclodextrin) was administered intraperitoneally at 1 h post-occlusion followed by subcutaneous injections at 6, 24 and 48 h post-occlusion. Measurements of infarct volumes (cortical, subcortical and total) were performed at 72 h and functional recovery, assessed by rotarod test, were performed 24, 48, and 72 h after pMCAO. Results: Following PROG treatment, stained sections revealed a significant reduction in cortical, caudate-putamen and hemispheric infarct volumes (% contralateral structure) compared to vehicle-injected controls. In addition, PROG treatment reduced functional deficits on the accelerating rotarod apparatus. Conclusion: We demonstrated and confirmed the neuroprotective effect of PROG using a permanent model of focal brain ischemia in rats. Show more

Keywords: Stroke, progesterone, pMCAO, neurosteroids, infarct volume, TTC, rotarod

Citation: Restorative Neurology and Neuroscience, vol. 25, no. 2, pp. 151-159, 2007

Authors: Gaillard, Frédéric

Article Type: Research Article

Abstract: Purpose: Fetal occipital allografts implanted into the posterior cortex of adult mice project massively throughout the ipsilateral pallium of the host, but rarely outside this domain (Gaillard et al., 2004). The present study was undertaken to examine in detail whether this pattern is specific to graft location. Methods: Cortical fragments corresponding to presumptive occipital areas were harvested from E15 mice fetuses expressing ubiquitously the eGFP protein, and implanted in correct (homotopic) and incorrect …(heterotopic) cortical loci in wild-type adults. Two months later, efferents were detected by immunohistochemistry and quantified on selected DAB-treated sections. Results: The present findings show (i) that robust projections are present in the ipsilateral host cortex regardless of the graft location; (ii) that 55% the grafts located in parietal and frontal cortices have obvious but sparse callosal and subcortical projections; and (iii) that grafts placed in occipital areas never contact ipsilateral subcortical targets, likely because graft-related axons are unable to cross obliquely the thalamocortical fascicles in the underlying white matter. Conclusions: These puzzling results question the use of transplantation strategies for repairing damaged networks in adults where rewiring involves complex white matter trajectories. Show more

Keywords: Transplantation, embryonic visual cortex, eGFP-expressing cells, mature brain, callosal projections, subcortical projections

Citation: Restorative Neurology and Neuroscience, vol. 25, no. 2, pp. 161-175, 2007

Authors: Mellough, Carla B. | Cui, Qi | Harvey, Alan R.

Article Type: Research Article

Abstract: Purpose: We tested whether microenvironmental changes surrounding apoptotic neural degeneration, cellular pre-treatment and timing of transplant can influence the survival and differentiation of transplanted cells. This was done by transplanting adult hippocampal precursor cells (AHPCs) into normal and retinal ganglion cell (RGC) depleted rat retinae. Methods: Apoptotic RGC death was induced in neonates by removal of the contralateral superior colliculus (SC) and in adults by unilateral optic nerve transection, with or …without a peripheral nerve (PN) graft. AHPCs were transplanted 24 h after SC ablation, or 5, 7 or 14 days following optic nerve (ON) transection. Hosts received untreated grafts, or grafts treated by co-culture with embryonic retinal explants or the neuropeptide somatostatin. Results: AHPCs integrated within all neonatal and 65% of adult retinae. Greater numbers of AHPCs were observed within the ganglion cell layer (GCL) in SC lesioned hosts. Explant co-culture induced proliferation of grafted AHPCs within host retinae. Somatostatin-treatment resulted in reduced overall engraftment but increased integration within the GCL. In lesioned adults, greatest GCL engraftment was observed following 7 or 14 day grafts. Some AHPCs in the inner retina expressed neuronal antigens and extended processes into the ON. Conclusions: These data indicate that various factors can influence the behaviour of grafted cells and work towards encouraging the functional restoration of retinal circuitry. Show more

Keywords: Adult hippocampal progenitors, ganglion cell depletion, optic nerve transection, retinal transplantation

Citation: Restorative Neurology and Neuroscience, vol. 25, no. 2, pp. 177-190, 2007