bluuebunny/crossref_metadata_2025 huggingface dataset:
Persistence of functional neuromuscular junctions formed in a denervated skeletal muscle of the adult rat by axons that have regrown from the injured spinal cord through a peripheral nerve autograft
Authors: Pécot-Dechavassine Monique , Horvat Jean-Claude , Mira Jean-Claude , Ye Jian Hui
Published: December 2019

In previous ‘short-term’ (2 to 7 months) experiments, we had demonstrated, in the adult rat, that motoneurons of the injured cervical spinal cord could extend lengthy axons into an autologous peripheral nerve segment which was connected to a nearby denervated skeletal muscle. In addition, we had shown that new functional motor endplates were formed by these axons both at the original sites of innervation and at ectopic locations of the denervated muscle. This substitution motor system, although quite functional, was anatomically very different from the original model of innervation in the intact animal, relating to its motoneuronal pool, the course of its motor axons and the sites of terminal innervation. The present ‘long-term’ (11 to 21 months) experiments demonstrate the anatomical and functional permanency of the new motor circuitry, despite a lack of strict specificity in the new neuromuscular connections. However, some minor modifications or adjustments were observed with time: (i) the maintenance of functional ectopic endplates could be consistently demonstrated, while functional reinnervated endplates at the initial sites of innervation were rare or even lacking; (ii) there was a definitive withdrawal of all non target-specific regenerated axons from the vicinity of the muscle. It is now necessary to address the question to what extent this substitution motor system is actually controlled by central and/or peripheral inputs.
The immunosuppressant FK506 increases functional recovery and nerve regeneration following peripheral nerve injury
Authors: Gold Bruce G. , Storm-Dickerson Toni , Austin Daniel R.
Published: December 2019

Regeneration of peripheral nerve fibers over long distances often requires extended periods of convalescence. Loss to society can be measured in terms of increased health care costs, decreased productivity and, in the case of job-related injuries, larger workers' compensation claims. The availability of drugs to increase axonal regeneration would be beneficial not only to patients but also to society in general by decreasing these costs. In the present paper, we present our initial studies on the regenerative effects of the new immunosuppressive agent FK506. Rats given a sciatic nerve crush (axotomy) received daily subcutaneous injections of FK506 (1.0 mg/kg); axotomized control animals received saline. Clinical signs of recovery in the hind feet were manifested two days earlier in FK506-treated than in saline-treated animals; movement in the toes, and walking on the hind feet and toes were observed at 16 and 17 days, respectively, in saline-treated rats and at 14 and 15 days, respectively, in FK506-treated rats. Measurement of interdigit distances in the hind feet at 18 days following axotomy showed a return toward normal position of the toes (increased interdigit distances) during walking in FK506-treated rats. Light and electron microscopy performed at 18 days following axotomy confirmed the clinical appearance of increased functional recovery in FK506-treated rats. Distal to the crush site, the sciatic nerve and its terminal branches from FK506-treated animals contained more myelinated fibers compared to saline-treated animals; in the soleus nerve, the numbers of myelinated axons was increased 2.75-fold. Taken together, the present results suggest that FK506 enhances recovery of function in the rat by increasing the rate of axonal regeneration following a sciatic nerve crush.
No adverse effects of cyclosporin A on cellular and functional development of foetal rat dopaminergic mesencephalic neurones grafted into the 6-hydroxydopamine rat model of Parkinson's disease
Authors: Earl Christopher D. , Frodl Eva M. , Pupeter Sigrid C. , Oertel Wolfgang H. , Kupsch Andreas
Published: December 2019

This study investigated the potential neurotoxic effects of cyclosporin A (CyA) on allogeneic foetal rat ventral mesencephalic (VM) grafts in the 6-hydroxydopamine rat model of Parkinson's disease. Despite its use in the clinical neural grafting situation, the safety of the CyA treatment concerning graft survival and function has not been demonstrated in systematical animal studies. Three groups of grafted rats were treated with either 10 or 20 mg/kg cylcosporin A daily for 6 weeks. Analysis of graft function and development within the different immunosuppression regimes showed no significant differences between any parameters assessed (rotational behaviour and graft survival). It is concluded that high doses of cyclosporin A do not adversely influence survival and function of rat-to-rat foetal allogeneic VM grafts.
Chronic alterations in rat brain α-adrenoceptors following traumatic brain injury
Authors: Levin Barry E. , Pan Shijun , Dunn-Meynell Ambrose
Published: December 2019

Norepinephrine (NE) has been implicated in cerebral plasticity and recovery of function after brain injury. To examine the status of noradrenergic mechanisms in the brain following traumatic brain injury (TBI), male Sprague-Dawley rats underwent right sensorimotor cortex contusions and were observed for the next 30 days for recovery of motor function by measurement of the time taken to perform a modified beam walking task! At 30 days, their brains were assayed by receptor autoradiography for αr- and α2-adrenoceptor binding with 1 nM [3H]prazosin and 1 nM [3H]paraminoclonidine, respectively. One day after contusion, TBI rats took 60% longer to run the beam than sham-lesioned controls. Run times were directly proportional (r = 0.784; P = 0.012) to lesion volume determined at 30 days. The motor deficit persisted for 8 days, after which TBI and control rats had similar run times, largely due to increased run times in sham rats. At 30 days, TBI rats had a generalized, bilateral decrease in [3H]prazosin binding across all brain areas read (F[l,13] = 9.23; P = 0.009) with specific 12%–21% decreases in the cortex contralateral to the lesion and bilaterally in the dorsomedial hypothalamic and three thalamic nuclei. On the other hand, [3H]paraminoclonidine binding did not differ from sham lesion controls in any brain area of TBI rats. Thus, unilateral TBI is followed by widespread, bilateral changes in α1-adrenoceptor binding which would leave the animal vulnerable to any factors which reduced the access of NE to its postsynaptic adrenoceptors. This is compatible with the observation that α1-antagonists and α2-agonists can transiently reinstate the motor deficit after recovery has occurred.
Rejection and regeneration through peripheral nerve allografts: immunoperoxidase studies with laminin, S100 protein and neurofilament antisera
Authors: Midha Rajiv , Mackinnon Susan E. , Evans Peter J. , Hunter Daniel A. , Becker Laurence E.
Published: December 2019

The pattern and temporal sequence of histopathological events in a rat nerve allograft model were evaluated. Following grafting and varying survival periods (from 1 to 30 weeks), the host and donor nerve were removed and assessed by light and electron microscopy. Nerve allografts underwent Wallerian degeneration and rejection. Wallerian degeneration was the dominant pathologic process at weeks 1 and 2 after engraftment. Histologic rejection started as an epineurial process at weeks I and 2, became progressively endoneurial and was most prominent at 4 and 6 weeks after engraftment. Rejection was accompanied by evidence of graft Schwann cell and endoneurial tube loss. The rejection process delayed, but did not prevent, nerve regeneration by the host. Regeneration of fine neurofilament-positive axonal sprouts into the proximal portions of the graft was observed as early as week 2. Subsequently, regeneration occurred through the periphery and around the exterior of the rejected nerve allograft fascicle. Regenerating axons were accompanied by S100 protein reactive Schwann cells and newly synthesized laminin-positive endoneurial tubes. Regenerating axons reinnervated the distal host segment at week 8 and increased in number and myelination thereafter. The observations of rejection and regeneration through nerve allograft segments are discussed in reference to previous studies.
Neuroprotection of completely lacerated spinal cord of adult rats by homotopic and heterotopic transplantation
Authors: Guizar-Sahagun Gabriel , Grijalva Israel , Madrazo Ignacio , Franco-Bourland Rebecca , Salgado-Ceballos Hermelinda , Ibarra Antonio , Larriva-Sahd Jorge
Published: December 2019

To evaluate the neuroprotective effect of transplants placed in the lesion zone after a complete spinal cord (SC) laceration, two independent series of experiments were carried out. In the first, allogeneic or xenogeneic fetal SC was transplanted into the gaps of the damaged lower thoracic SC of adult rats. In the transplanted rats the incidence of life-threatening complications was reduced, and the survival rate was increased compared with the control group (lesion, without implant). Histological examination showed less damage to the neighboring SC parenchyma in the transplanted rats. The measurement of this neuroprotective effect was made in a second series of experiments. Using the same model of SC injury, allogeneic fetal SC, autologous peripheral nerve and/or adipose tissue were implanted. Rats with implants of Gelfoam and damaged rats without implants were the controls. The implanted rats of all groups, including the Gelfoam group, showed a better survival rate than the nonimplanted rats. Significantly less damage to the neighboring SC parenchyma was measured in implanted rats with any of the live tissues tested compared with non-implanted rats, although no significant differences were observed between the Gelfoam group and the nonimplanted rats. Histological evidence of tissue implant survival was observed in all corresponding groups. It is concluded that the transplanted tissues tested here have a neuroprotective effect, possibly by acting as a buffer to neurotoxic substance(s) released by the stumps, and/or by exerting trophic effect(s) on the host.
Neurotrophic effect of submicrosomal fractions obtained from pre-degenerated peripheral nerves
Authors: Lewin-Kowalik Joanna , Barski Jaroslaw-Jerzy , Krause Mieczyslaw , Górka Dariusz , Golka Beata , Larysz-Brysz Magdalena
Published: December 2019

Submicrosomal fractions obtained from pre-degenerated distal stumps of sciatic nerves were implanted by means of connective tissue chambers into the injured hippocampus for 8 and 18 weeks. The nerve stumps were allowed to pre-degenerate for 7, 28 and 35 days. The neuronal outgrowth was examined by means of FITC-HRP injected into the chamber. Eight weeks postoperatively the greatest number of traced cells was present in brains treated with the fraction obtained from nerves pre-degenerated for 7 days. Eighteen weeks following implantation the greatest number of FITC-HRP positive cells was found in brains grafted with the fraction from nerves pre-degenerated for 35 days.
Forebrain and midbrain astrocytes promote neuritogenesis in cultured chromaffin cells
Authors: Colombo Jorge A. , Napp Mónica
Published: December 2019

Adrenal chromaffin cells from immature or adult rats were grown in one of the following ‘in vitro’ conditions: (1) on coverslips placed on top of confluent, fetal, regional glia cultures; (2) in conditioned media from similar confluent cultures; (3) after direct seeding on top of such confluent cultures. Astroglia was obtained from cerebral cortex, septum, striatum and ventral mesen-cephalon from El6-17 pregnant-dated rats. All regions succesfully generated conditions for the early (less than 24 h) expression of neuritogenesis in about 15% of cells, which was more apparent in immature adrenal cell dissociates than in adult ones. The former grew long neurites compared with their adult counterparts. In addition to the known effects of glioma conditioned medium and isolated trophic factors described by other authors, it is concluded that adrenal chromaffin cells are responsive to the neuritogenic activity of (central) astroglial diffusible factor(s) in non-supplemented, defined culture media conditioned by astrocytes from various brain regions. Additionally, evidence is offered that adult chromaffin cells show a reduced responsiveness towards such astroglial factor(s). Possible implications for cell trasplantation chimeras are discussed.
Engineered cells: a promising therapeutic approach for neural disease
Authors: Fisher Lisa J.
Published: December 2019

The transplantation technique has been invaluable for studying the CNS. Recently, the use of genetically modified cells for CNS grafting has further increased the utility of this technique. Studies conducted during the past 10 years have shown that a variety of genes can be successfully expressed in both neural and non-neural populations. Depending on the cell type used for gene transfer, engineered cells survive well within the CNS and continue to synthesize engineered products. In addition to providing insights into CNS development and plasticity, genetically modified cells have revealed the therapeutic role of different factors in neural disease. Cells engineered to produce growth factors have been shown to prevent and/or minimize neural degeneration following an experimental damage while the intracerebral transplantation of cells genetically modified to produce neurotransmit-ters have successfully reversed behavioral impairments of animals with experimental Parkinson's disease or Alzheimer's disease. Recent results with engineered cells transplanted into the brain of non-human primates suggest the potential of engineered cells for human therapy. Work with encapsulation techniques to isolate engineered cells from a host brain offers one of several approaches for ensuring the safety of genetically modified cells grafted into the CNS. Identifying factors that influence the survival and gene expression of engineered cells following transplantation will enhance the usefulness of these cells for studying and repairing the CNS.
Effects of delayed nerve repair on regeneration of rat sciatic nerve
Authors: Urabe Tadahisa , Zhao Qing , Lundborg Göran , Danielsen Nils
Published: December 2019

The optimal time for nerve suture in transected rat sciatic nerve was investigated. The sciatic nerve on both side nerves were transected and repaired by an epineurial suture technique 0–28 days after nerve transection. The regeneration distance was measured by the sensory pinch reflex test 2–6 days after nerve repair. The initial delay period and the regeneration rate were calculated by using a new mathematical model. One day delayed repair was sufficient to reduce the initial delay period and the largest reduction on the initial delay period was observed in the three day delayed repair group. The initial delay period was reduced to 0.87 days as compared to 2.31 days for nerves repaired immediately (controls). The seven day and ten day delayed repair had similar effects but they also showed a decrease of the regeneration rate. The regeneration rate was not affected except for these two time points. The results suggest that the repair delay period can influence the initial delay as well as the regeneration rate. In our model an optimal effect was achieved on both these measures with a one or three day delay between transection and repair.
Asymmetrical behavior in rats following striatal lesions and fetal transplants: the elevated body swing test
Authors: Borlongan Cesario V. , Cahill David W. , Sanberg Paul R.
Published: December 2019

Animals with unilateral neurotoxic lesions in the striatum exhibit a stereotypical biased rotational behavior in response to dopamine agonists. We recently argued that the rotational test may be subject to sensitization effects of the drug. Accordingly, we proposed the drug-free elevated body swing test (EBST) as an alternative behavioral index of motor asymmetry in striatal lesioned animals. EBST involves elevating the animal from the ground by holding its tail and simply recording the number of swings to either side made by the animal over 30 s. We previously reported that Sprague–Dawley, male 8-week-old rats, intrastriatally lesioned with 500 nanomoles of 3-nitropropionic acid or 225 nanomoles of quinolinic acid, exhibit biased swing activity at 7, 14, 21 and 28 days post-lesion. In the present study, we extended the efficacy of the EBST in measuring the recovery of motor function following fetal striatal transplants. At 2 months post-lesion, lesioned animals which show 70% or higher biased swing activity were transplanted with rat fetal striatal lateral eminence (16-day-old gestational age). When tested in the EBST at 1 and 3 months post-transplant, these transplanted animals displayed normalization of the biased swing activity. In contrast, animals transplanted with medium alone continued to exhibit a biased swing activity. The present study thus extends our previous EBST data to include successful behavioral characterization by EBST of recovery of motor function in lesioned animals receiving fetal transplants.
Amphetamine affects the behavioral outcome of lateral fluid percussion brain injury in the rat
Authors: Prasad Renuka M. , Dose John M. , Dhillon Harbhajan S. , Carbary Timothy , Kraemer Philipp J.
Published: December 2019

This study examined the effects of (D)-amphetamine, methoxamine (an al-adrenergic receptor agonist), and prazosin (an al-adrenergic receptor antagonist) on the behavioral outcome of lateral fluid percussion brain injury. Rats trained to perform a beam walking task were subjected to brain injury of moderate severity (2.1–2.2 atm). At 10 min after injury, rats were treated with amphetamine, methoxamine or prazosin at two different dose levels. Amphetamine-treated animals displayed significantly lower impairment in beam walking ability from days 1 to 5 after brain injury. Neither methoxamine nor prazosin significantly affected the impairment in beam walking ability from day 1 to day 7 after injury. However, prazosin treatment at both dose levels increased the post-injury mortality and the incidences of failure to recovery from hemiplegia. Amphetamine-treatment at 4 mg/kg, but not at 2 mg/kg, improved the spatial learning abilities of the injured animals. Neither methoxamine nor prazosin affected the spatial learning abilities. These results indicate that amphetamine facilitated beam walking recovery and improved cognitive function after concussive fluid percussion injury. Although the methoxamine experiments suggest that the norepinephrine-α1-adrenergic receptor system may not be involved in the pathophysiology of fluid percussion brain injury, our results with amphetamine (beneficial effects) and prazosin (deleterious effects) and the results observed in other models of brain injury point out that further investigations are necessary to understand the role of a1-adrenergic receptors in brain injury.
Metabolic profile of fetal dopamine neurons transplanted to the adult rat striatum
Authors: Silverman William F. , Solberg Yoram , Pollack Yaakov
Published: December 2019

In the present study, we have examined the expression and distribution of the metabolic marker neuron-specific enolase (NSE) in solid-tissue transplants of fetal substantia nigra (SN) to the striatum of intact and 6-hydroxydopamine lesioned mature rats. Immunocytochemistry was applied to label NSE and tyrosine hydroxylase (TH) respectively. Cellular content of NSE is indicative of metabolic activity as well as synaptogenesis/maturation. Three months after implantation, the fetal grafts exhibited intensely TH-immunoreactive neurons, typically organized in elongated clusters, especially along the graft–host border and along blood vessels penetrating into the graft interior. Moderate to high metabolic activity as indicated by NSE immunoreactivity was observed in neuronal perikarya, principally in non-TH immunoreactive areas. In contrast to these immunohistochemical findings, in situ hybridization for TH mRNA, carried out exclusively on grafts into the intact striatum, demonstrated DA cell bodies both at the graft–host interface and, significantly, throughout the graft interior. The number of transcripts per cell, moreover, did not differ significantly in these two locations. We propose that conditions at the graft–host border promote tissue-specific regulation of nigral DA neurons, and that this regulation occurs post-transcriptionally. Thus, DA neurons relatively distant from the host parenchyma are underregulated, resulting in a higher level of metabolic activity and an increased turnover of TH in the grafted neurons.
Localization of gliosis in the corpus striatum of mice following cortical lesions
Authors: Khoja I. , Herranz A.S. , Williams J.R. , Cannon-Spoor H.E. , Heim R.C. , Freed W.J. , Poltorak M.
Published: December 2019

Localized lesions of the medial and lateral frontal cortex were used to study gliosis, neurofilament content and changes in synaptic density in the mouse striatum. Relationships between the sites of cortical lesions and the localization of changes in different regions of the striatum were examined after 3 and 12 weeks. Independent of the location of frontal cortex lesions, glial fibrillary acidic protein (GFAP) immunoreactivity was increased throughout the entire striatum after 3 weeks. Twelve weeks after lesioning, increases in GFAP were confined to the dorsomedial (DM) striatum following medial cortical lesions, and to the dorsolateral (DL) striatum following lateral cortical lesions, suggesting persistent gliosis only in areas of striatal deafferentation. It appears, therefore, that the mechanisms which induce gliosis after short and long time periods are different.
Expression of choline acetyltransferase within spinal motoneurons following brachial plexus avulsion
Authors: Wu Yangguan , Han Kai , Wu Wutian , Terzis Julia K.
Published: December 2019

Avulsion of the brachial plexus is considered the most severe injury of the peripheral nerve. The present study provides a description of the response of ChAT within the ventral horn of the rat cervical spinal cord following avulsion of the brachial plexus. The result demonstrates that the intensity of immunoreactivity of ChAT positive neurons and neuropil background increases in the first 3 days following avulsion and then decreases. The number of ChAT-positive motorneurons in the ventral horn in the lesion side is 84.4% compared to the normal side during the first 3 days post-avulsion, at 7 days the number of ventral horn neurons drops to 64.4% and at 21 days post-avulsion it becomes 44.1%. In the sixth week post-avulsion, only 24.8% of the ventral horn neurons still persist.
Specificity of fiber innervation by cholinergic neurons transplanted into the retrosplenial cortex of adult rats as revealed by choline acetyltransferase immunocytochemistry
Authors: Li Ying J. , Hartman Boyd K. , Faris Patricia L. , Low Walter C.
Published: December 2019

The retrosplenial cortex (RSC) is a target of the forebrain cholinergic projecting system. It receives extensive cholinergic innervation from the medial septal nucleus and the diagonal band of Broca. These cholinergic afferents travel along the paths of cingulate bundle and fornix. In the present study we investigated the ability of cholinergic fetal septal grafts to reinnervate the deafferented RSC. Four groups of rats were used: (1) normal control rats (NC); (2) rats with bilateral transections of the cingulate bundle (CgX); (3) rats with simultaneous lesions of both the cingulate bundle and the fornix (FX), and (4) rats with intra-retrosplenial fetal septal grafts and lesions in both cingulate bundle and the fornix (RSCsep-TPL). We found that lesions in the cingulate bundle alone produced a modest reduction of cholinergic innervation whereas lesions in both the fornix and cingulate bundle resulted in a complete loss of cholinergic inputs in this area, indicating that both the cingulate bundle and the fornix are involved in mediating cholinergic projections from the septal-diagonal area to the RSC. Transplantation of cholinergic fetal septal neurons into the RSC of animals with simultaneous lesions in both the fornix and cingulate bundle restored the cholinergic innervation pattern to that which is typical of the normal septo-retrosplenial inputs. These results provide the neuroanatomical basis for behavioral studies which have documented graft-mediated recovery of spatial memory function in rats with lesions of the cholinergic septo-retrosplenial pathways
Nimodipine-accelerated hypoglossal sprouting prevents the postoperative hyperinnervation of target muscles after hypo glossal-facial anastomosis in the rat
Authors: Angelov Doychin N. , Neiss Wolfram F. , Gunkel Andreas , Streppel Michael , Guntinas-Lichius Orlando , Stennert Eberhard
Published: December 2019

Hypoglossal-facial anastomosis (HFA), used for the treatment of facial palsy, was performed in adult Wistar rats. For 7–224 days post operation (DPO), half of the animals were kept on standard laboratory food and half received food pellets containing 1000 ppm of the Ca2+ channel blocker nimodipine. The postoperative neurotization of facial muscles in these two groups was traced by comparing numbers of all retrogradely labeled neurons after injection of HRP into the whiskerpad muscles. In unoperated animals, injection of HRP labeled 1254 ± 54 neurons. Immediately after HFA, this number dropped to zero. The treatment with nimodipine yielded two beneficial effects. (1) In the early phase of regeneration (until 28 DPO), it accelerated the sprouting of hypoglossal axons into the facial periphery; (2) In the final phase, it suppressed the axonal sprouting from both, hypoglossal and facial stumps. In this way nimodipine fully prevented the postoperative hyperinnervation, i.e. the projection of more hypoglossal plus facial motoneurons to the whiskerpad muscles than under normal conditions.
Mechanisms of gender-linked ischemic brain injury
Authors: Liu Mingyue , Dziennis Suzan , Hurn Patricia D. , Alkayed Nabil J.
Published: December 2019

Biological sex is an important determinant of stroke risk and outcome. Women are protected from cerebrovascular disease relative to men, an observation commonly attributed to the protective effect of female sex hormones, estrogen and progesterone. However, sex differences in brain injury persist well beyond the menopause and can be found in the pediatric population, suggesting that the effects of reproductive steroids may not completely explain sexual dimorphism in stroke. We review recent advances in our understanding of sex steroids (estradiol, progesterone and testosterone) in the context of ischemic cell death and neuroprotection. Understanding the molecular and cell-based mechanisms underlying sex differences in ischemic brain injury will lead to a better understanding of basic mechanisms of brain cell death and is an important step toward designing more effective therapeutic interventions in stroke.
Visual perceptual learning is similar across the extrafoveal	central visual fields
Authors: Neary K. , Anand S. , Hotson J.R.
Published: December 2019

Purpose: Visual perceptual learning occurs with the presentation of novel visual stimuli at retinal sites near the fovea to 20° eccentricities. It was unclear if the magnitude and rate of visual learning were similar across the central visual fields or if visual learning decreased with increasing eccentricity. The robustness of learning across the visual fields may affect the magnitude of computer-aided visual recovery after visual brain injury. Therefore we determined if eccentricity was a factor that influenced perceptual learning.

Methods: Subjects were trained to detect the presence or absence of a single line oriented differently (odd-element) from an array of lines that otherwise had the same orientation. The odd-element line was presented 3°, 9° or 18° from fixation.

Results: Perceptual performance improved during training trials with a similar magnitude and similar learning curve slopes at all 3 eccentricities. Pre- and post-training performance improved to a similar magnitude at 3 vs 9° in 4 of 4 subjects tested and at 9° vs 18° in 4 of 5 subjects. In the fifth subject there was no post-training improvement in performance at 18°.

Conclusion: Visual perceptual learning is similar across the extrafoveal central visual fields in almost all subjects.
Efficacy of EMG-triggered electrical arm stimulation in chronic	hemiparetic stroke patients
Authors: von Lewinski Friederike , Hofer Sabine , Kaus Jürgen , Merboldt Klaus-Dietmar , Rothkegel Holger , Schweizer Renate , Liebetanz David , Frahm Jens , Paulus Walter
Published: December 2019

Purpose: EMG-triggered electrostimulation (EMG-ES) may improve the motor performance of affected limbs of hemiparetic stroke patients even in the chronic stage. This study was designed to characterize cortical activation changes following intensified EMG-ES in chronic stroke patients and to identify predictors for successful rehabilitation depending on disease severity.

Methods: We studied 9 patients with severe residual hemiparesis, who underwent 8 weeks of daily task-orientated multi-channel EMG-ES of the paretic arm. Before and after treatment, arm function was evaluated clinically and cortical activation patterns were assessed with functional MRI (fMRI) and/or transcranial magnetic stimulation (TMS).

Results: As response to therapy, arm function improved in a subset of patients with more capacity in less affected subjects, but there was no significant gain for those with Box & Block test values below 4 at inception. The clinical improvement, if any, was accompanied by an ipsilesional increase in the sensorimotor cortex (SMC) activation area in fMRI and enhanced intracortical facilitation (ICF) as revealed by paired TMS. The SMC activation change in fMRI was predicted by the presence or absence of motor-evoked potentials (MEPs) on the affected side.

Conclusions: The present findings support the notion that intensified EMG-ES may improve the arm function in individual chronic hemiparetic stroke patients but not in more severely impaired individuals. Functional improvements are paralleled by increased ipsilesional SMC activation and enhanced ICF supporting neuroplasticity as contributor to rehabilitation. The clinical score at inception and the presence of MEPs have the best predictive potential.
Raised corticomotor excitability of M1 forearm area following	anodal tDCS is sustained during robotic wrist therapy in chronic stroke
Authors: Edwards D.J. , Krebs H.I. , Rykman A. , Zipse J. , Thickbroom G.W. , Mastaglia F.L. , Pascual-Leone A. , Volpe B.T.
Published: December 2019

Anodal transcranial direct current stimulation (tDCS) can transiently increase corticomotor excitability of intrinsic hand muscles and improve upper limb function in patients with chronic stroke. As a preliminary study, we tested whether increased corticomotor excitability would be similarly observed in muscles acting about the wrist, and remain present during robotic training involving active wrist movements, in six chronic stroke patients with residual motor deficit.

Methods: Transcranial magnetic stimulation (TMS) generated motor evoked potentials (MEP) in the flexor carpi radialis (FCR) and provided a measure of corticomotor excitability and short-interval cortical inhibition (SICI) before and immediately after a period of tDCS (1 mA, 20 min, anode and TMS applied to the lesioned hemisphere), and robotic wrist training (1hr).

Results: Following tDCS, the same TMS current strength evoked an increased MEP amplitude (mean 168 ± 22%SEM; p < 0.05), that remained increased after robot training (166 ± 23%; p < 0.05). Conditioned MEPs were of significantly lower amplitude relative to unconditioned MEPs prior to tDCS (62 ± 6%, p < 0.05), but not after tDCS (89 ± 14%, p = 0.40), or robot training (91 ± 8%, p = 0.28), suggesting that the increased corticomotor excitability is associated with reduced intracortical inhibition.

Conclusion: The persistence of these effects after robotic motor training, indicates that a motor learning and retraining program can co-exist with tDCS-induced changes in cortical motor excitability, and supports the concept of combining brain stimulation with physical therapy to promote recovery after brain injury.
A virtual reality-based system integrated with fmri to study	neural mechanisms of action observation-execution: A proof of concept	study
Authors: Adamovich S.V. , August K. , Merians A. , Tunik E.
Published: December 2019

Purpose: Emerging evidence shows that interactive virtual environments (VEs) may be a promising tool for studying sensorimotor processes and for rehabilitation. However, the potential of VEs to recruit action observation-execution neural networks is largely unknown. For the first time, a functional MRI-compatible virtual reality system (VR) has been developed to provide a window into studying brain-behavior interactions. This system is capable of measuring the complex span of hand-finger movements and simultaneously streaming this kinematic data to control the motion of representations of human hands in virtual reality.

Methods: In a blocked fMRI design, thirteen healthy subjects observed, with the intent to imitate (OTI), finger sequences performed by the virtual hand avatar seen in 1st person perspective and animated by pre-recorded kinematic data. Following this, subjects imitated the observed sequence while viewing the virtual hand avatar animated by their own movement in real-time. These blocks were interleaved with rest periods during which subjects viewed static virtual hand avatars and control trials in which the avatars were replaced with moving non-anthropomorphic objects.

Results: We show three main findings. First, both observation with intent to imitate and imitation with real-time virtual avatar feedback, were associated with activation in a distributed frontoparietal network typically recruited for observation and execution of real-world actions. Second, we noted a time-variant increase in activation in the left insular cortex for observation with intent to imitate actions performed by the virtual avatar. Third, imitation with virtual avatar feedback (relative to the control condition) was associated with a localized recruitment of the angular gyrus, precuneus, and extrastriate body area, regions which are (along with insular cortex) associated with the sense of agency.

Conclusions: Our data suggest that the virtual hand avatars may have served as disembodied training tools in the observation condition and as embodied "extensions" of the subject's own body (pseudo-tools) in the imitation. These data advance our understanding of the brain-behavior interactions when performing actions in VE and have implications in the development of observation- and imitation-based VR rehabilitation paradigms.
Working memory training in patients with multiple sclerosis –	comparison of two different training schedules
Authors: Vogt Annamarie , Kappos Ludwig , Calabrese Pasquale , Stöcklin Markus , Gschwind Leo , Opwis Klaus , Penner Iris-Katharina
Published: December 2019

Purpose: Evaluation of two different training schedules of a computer based working memory training (BrainStim) in patients with multiple sclerosis (MS).

Method: Forty-five MS outpatients were allocated to two different training groups and a control group without training. Patients with treatment received 16 training sessions scheduled either as a high intensity training (4 times per week for 4 weeks) or as a distributed training (2 times per week for 8 weeks). A neuropsychological test battery including self-report measures was applied at baseline and at retest. The baseline assessment was performed twice at an interval of two weeks to control for possible learning effects.

Results: In the outcome measures training for both intervention groups led to significantly improved fatigue symptoms as well as working memory -, and mental speed performances. Log files recorded during training showed a similar increase in levels of difficulty for both intervention groups as training progressed. No effects were found on short term memory, quality of life or depression.

Conclusions: Since comparable improvements were observed in both training groups, BrainStim can be applied as a therapeutic intervention adjusted to the personal agenda of MS patients.
Long-term levodopa admnistration in chronic stroke patients. A	clinical and neurophysiologic single-blind placebo-controlled cross-over pilot	study
Authors: Acler M. , Fiaschi A. , Manganotti P.
Published: December 2019

Purpose: Promising new rehabilitative approaches to improve the substantial motor disability associated with chronic stroke include pharmacotherapy to enhance motor recovery. We conducted a single-blind placebo-controlled crossover pilot study to investigate the effects of prolonged treatment with L-DOPA in stroke patients.

Methods: Ten chronic (10–48 months) stroke patients received placebo or L-DOPA 100 mg daily for 5 weeks. During drug's treatment patients suspended physiotherapy. Patients underwent clinical evaluation (Rivermead Motor Assessment, Nine Hole Peg Test, and 10 meter walking test) and transcranial magnetic stimulation recordings from the affected and unaffected hemisphere (resting motor threshold, motor evoked potential amplitude and cortical silent period) before and after 5 weeks of treatment.

Results: After L-DOPA treatment patients improved their walking speed (p< 0.01) and manual dexterity (p< 0.01) with the affected hand, the cortical silent period over the affected hemisphere lengthened (p< 0.01), while no changes were found in placebo-group.

Conclusion: A 5-week course of oral L-DOPA in a single daily dose substantially improves motor performance in patients with chronic stroke and could do so by modulating motor cortical excitability (cortical silent period lengthening) suggesting that cortical inhibitory mechanisms have a role in motor recovery after stroke. Pharmacotherapy could be a useful therapeutic approach for chronic stroke patients.
Drug screening of neuroprotective agents on an organotypic-based	model of spinal cord excitotoxic damage
Authors: Guzmán-Lenis Mónica-Sofía , Navarro Xavier , Casas Caty
Published: December 2019

Purpose: Damage to segmental motoneurons and to spinal cord parenchyma cause denervation atrophy to the muscles, contributing to the chronic disability originated by spinal cord injury (SCI) and spinal motor neuron diseases. After SCI, damage is promoted by several underlying mechanisms, including release of glutamate and consequent over-activation of glutamate receptors, mainly NMDA receptors, that lead to neuronal death. Due to the lack of effective treatments for such conditions, new alternatives need to be explored.

Methods: In order to perform a relatively quick and high-fidelity drug screening, we optimized a postnatal rat organotypic spinal cord culture. By using a glutamate excitotoxic model of spinal cord damage on the explants, we compared the neuroprotective efficacy of four agents: methylprednisolone, erythropoietin, riluzole and rolipram. We evaluated the number of surviving ventral motor neurons stained with the SMI32 antibody and estimated the cord tissue preservation by quantifying the amount of EthD fluorescent probe incorporated into the cells.

Results: The best tissue protection was achieved with riluzole (98%) whereas the highest motoneuron preservation was obtained with methylprednisolone (92%).

Conclusion: The in vitro model used may serve to initiate comparative analyses of new compounds to narrow the choice for future neuroprotective agents to be tested in vivo.
Restoration of electroretinogram activity in exenterated swine	eyes following ophthalmic artery anastomosis
Authors: Shi Jun , Ellenberg David , Kim Jae Yong , Qian Haohua , Ripps Harris , Jain Sandeep , Chang Jin-Hong , Azar Dimitri T.
Published: December 2019

Purpose: To determine the feasibility of restoring electroretinogram (ERG) activity of exenterated swine eyes following in vivo arterial anastomosis.

Methods: The carotid artery was exposed and cannulated. The eye was exenterated along with the extraocular muscles and surrounding connective tissue. Prior to eye transplantation, the ophthalmic artery was identified and anastomosed to the carotid artery. Perfusion was confirmed by injecting FITC-conjugated tomato lectin into the anastomotic tubing and performing confocal microscopy of retinal flat-mounts. Dark-adapted ERG and optic nerve responses were analyzed to assess retinal function, and dilated eye examination and retinal imaging were performed.

Results: Arterial anastomosis resulted in perfusion of blood from the carotid artery through the anastomosis and into the ophthalmic artery. Arterial perfusion was confirmed by the presence of tomato lectin-stained retinal vessels. Immediately following the anastomosis, ERG and optic nerve activities were minimal. However, an "a" wave (representing photoreceptor activity), "b" wave (representing bipolar cell activity), and optic nerve responses (representing RGC activity) were detected 30 min after reperfusion.

Conclusions: Electroretinographic function is partially recovered following re-anastomosis of exenterated swine eyes. This model would be useful for further studies on eye transplantation.
Can we change brain functioning with cognition-focused	interventions in Alzheimer's disease? The role of functional neuroimaging
Authors: van Paasschen Jorien , Clare Linda , Woods Robert T. , Linden David E.J.
Published: December 2019

Purpose: This review considers the application of functional magnetic resonance imaging (fMRI) to identify treatment effects and brain plasticity in cognition-focused interventions aimed at people with Alzheimer's disease (AD). At present there is little evidence available that bears directly on this question. Associative memory function is affected in the early stages of AD and also deteriorates disproportionately in comparison to other types of memory in healthy ageing.

Methods: We review paradigms from the literature on face-name learning in fMRI in three groups (AD, mild cognitive impairment, and healthy ageing) with the aim of developing a paradigm to measure treatment effects and functional plasticity following cognitive intervention.

Results: Previous studies have commonly selected participants with high levels of education, and have generally used challenging tasks, with considerable variations in level of task performance across studies. The findings of the review indicate that there is a need a simple face-name learning paradigm that can be used with people with AD, and which can be applied either as a single assessment tool to compare various subject groups or as an outcome tool to assess functional changes following a period of cognitive intervention.

Conclusions: We make recommendations for such a paradigm and discuss pilot data showing the successful application of our paradigm in an individual with MCI.
Far transfer in cognitive training of older adults
Authors: Zelinski Elizabeth M.
Published: December 2019

Purpose: This article reviews the literature on far transfer effects in training of older adults.

Methods: Adapting a taxonomy of transfer developed by Barnett and Ceci (2002), to rehabilitation or enhancement of existing cognitive skills; results of studies assessing transfer effects from training of memory, reasoning, UFOV, dual task performance, and complex training are classified.

Results: Comparisons of the transfer outcomes of both strategy training and extended practice approaches suggest that far transfer has been observed.

Conclusions: Outcomes for strategy studies training memory have had less success than extended practice studies in obtaining far transfer. Reasons for this are discussed, as are suggestions for improved assessment of transfer outcomes.
Is adaptive neuronal plasticity an epiphenomenon of the	BOLD-signal?
Authors: Marcar Valentine L.
Published: December 2019

Purpose: This paper will examine different neurocognitive theories which conclude that the brain is able to restore or redress lost or damaged processing systems by reorganising remaining neuronal resources.

Method: The blood oxygenation level dependent or BOLD-signal is the most frequently used method for imaging brain activity in healthy, young adults, children, the elderly, or subjects with a neurodegenerative condition. The BOLD-signal reflects the balance between oxygen metabolism and vascular blood supply. The effect of neuronal discharge activity and neuronal recruitment on oxygen metabolism and vascular blood supply will be described.

Result: Maturation, senescence or degenerative illness alter the balance of oxygen metabolism and vascular blood supply on a regional level. This changes the ability to detect brain activity using the BOLD-signal and accounts for the activation pattern observed in the young, the old and the ill.

Conclusions: The change in activation pattern observed in the young, the old and the ill is not the result of a compensatory mechanism but the result of a disparity in the neuronal process which can not be compensated for.
The plastic human brain
Authors: Jäncke Lutz
Published: December 2019

Purpose: In this review I summarize and discuss reported findings of structural and functional plasticity in the intact human brain.

Methods: The main focus is placed on research that uses musicians as a model to study brain plasticity. I summarize therefore mostly studies dealing with musicians or with the effect of music practice. In the first section, structural plasticity is described on the basis of modern neuroanatomical studies using magnetic resonance imaging (MRI) techniques. In the second part, emphasis is given to studies reporting functional plasticity on the basis of changed neurophysiological activation patterns. These studies are discussed in the context of two approaches employed to study plasticity in the human brain: the cross-sectional and longitudinal approaches.

Results: The reviewed studies altogether indicate that experience can shape brain anatomy and brain physiology. Brain plasticity as demonstrated here is related to changed grey and white mater densities (and volumes) but also to changed activation patterns in the brain areas involved in controlling the expertise task.

Conclusions: Taken together, all studies support the view that the human brain is much more plastic than had been anticipated 20 years ago
Human embryonic stem cells: Derivation, culture, and differentiation: A review
Authors: Vazin Tandis , Freed William J.
Published: December 2019

The greatest therapeutic promise of human embryonic stem cells (hESC) is to generate specialized cells to replace damaged tissue in patients suffering from various degenerative diseases. However, the signaling mechanisms involved in lineage restriction of ESC to adopt various cellular phenotypes are still under investigation. Furthermore, for progression of hESC-based therapies towards clinical applications, appropriate culture conditions must be developed to generate genetically stable homogenous populations of cells, to hinder possible adverse effects following transplantation. Other critical challenges that must be addressed for successful cell implantation include problems related to survival and functional efficacy of the grafted cells. This review initially describes the derivation of hESC and focuses on recent advances in generation, characterization, and maintenance of these cells. We also give an overview of original and emerging differentiation strategies used to convert hESC to different cell types. Finally, we will discuss transplantation studies of hESC-derived cells with respect to safety and functional recovery.