bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of hemispatial neglect by means of rTMS – a review
Authors: Cazzoli Dario , Müri René M. , Hess Christian W. , Nyffeler Thomas
Published: December 2019

Hemispatial neglect – defined as the failure to attend, explore, and act upon the contralesional side of space – is a frequent and disabling neurological syndrome. Interhemispheric rivalry is considered as a major pathophysiological mechanism underlying hemispatial neglect. According to this account, the contralesional, intact hemisphere undergoes a pathological hyperactivity due to a deficient transcallosal inhibition from the damaged hemisphere. This model offers a framework for possible therapeutic interventions with repetitive transcranial magnetic stimulation (rTMS), i.e. a reduction of the pathological hyperactivity with a rTMS protocol that has lasting inhibitory effects. In the present work, we will first review evidence for the interhemispheric rivalry account coming from animals and humans. We will then describe studies showing the possibility to perturb and to restore interhemispheric balance in healthy subjects as a proof of concept for therapeutic rTMS application. Finally, we will consider studies applying rTMS as a therapeutic approach in hemispatial neglect. We conclude that rTMS is a promising approach to reduce the interhemispheric imbalance in neglect patients and to ameliorate symptoms. Newly developed protocols such as Theta Burst Stimulation (TBS) – with short stimulation times and long offline effects – seem to be particularly convenient. However, future studies should assess stimulation effects not only in clinical testing, but also on disability, considering combination with traditional therapies as well.
Transcranial magnetic stimulation in depression – Lessons from	the multicentre trials
Authors: Schönfeldt-Lecuona C. , Cárdenas-Morales L. , Freudenmann R. W. , Kammer T. , Herwig U.
Published: December 2019

Looking at novelties and advances in medicine in particular in the treatment of major depressive disorder no principally new antidepressant treatment strategy has been established in clinical routine in the last fifty years. However, regarding the considerable issue of treatment resistance in depression, new therapeutic strategies are urgently required. In this context, repetitive transcranial magnetic stimulation above the dorsolateral prefrontal cortex has been proposed as a potential new treatment option for depression; furthermore, in October 2008 a first rTMS-device (NeuroStar TMS Therapy System™) was approved by the FDA for the treatment of treatment resistant major refractory depression in adults. Yet, despite now nearly two decades of research in this field, no final answer concerning its validity for antidepressant treatment in the clinical practice is given. Numerous studies with small sample sizes and heterogeneous designs have been performed in this field yielding to different results. These were subjected to meta-analyses, assessing the antidepressant effect of rTMS, which are briefly summarized in this article. Further, multicentre-trials with larger numbers of patients were performed, which are presented and critically discussed here in more detail. This short review shall thus provide an overview of the current status of knowledge concerning rTMS in depression and it also provides some recommendations for future research in this field.
Effect of slow repetitive TMS of the motor cortex on ipsilateral	sequential simple finger movements and motor skill learning
Authors: Kobayashi Masahito
Published: December 2019

Background: Disruption of a cortical region can paradoxically improve behavior. After unilateral damage to the primary motor cortex (M1), increased excitability of the unaffected M1 has been shown. The M1 plays a critical role in motor performance and also early aspects of motor skill learning. Repetitive transcranial magnetic stimulation (rTMS) of one motor cortex can lead a temporary reduction in cortical excitability. We hypothesize that unilateral suppression of one M1 by rTMS may increase excitability of the unaffected motor cortex and thus improve motor performance and motor skill learning with the ipsilateral hand by releasing the contralateral motor cortex from transcallosal inhibition.

Methods: Forty healthy volunteers participated in our study; 16 for the experiment I and 24 for the experiment II. In the experiment I, after practicing a sequential simple key-pressing task with the index finger, their motor performance was monitored before and after slow-frequency (1Hz) rTMS, applied on the M1 ipsilateral or contralateral to the hand, ipsilateral premotor area or vertex (Cz). In the experiment II, participants were randomly divided into three stimulation groups: i) ipsilateral M1; ii) contralateral M1; and iii) Cz. rTMS was applied before the initiation of practice and learning of a simple motor skill. Mean execution time and error rate were recorded in 4 sessions distributed over 2 days.

Results: In experiment I: rTMS of M1 shortened execution time of the motor task with the ipsilateral hand, without affecting performance with the contralateral hand. This effect outlasted rTMS by at least 10 min, and was most prominent for M1 stimulation. In experiment II, disruption of M1 with rTMS slowed down skill acquisition with the contralateral hand, but paradoxically accelerated learning with the ipsilateral hand. This effect was evident during the first of 2 days of practice in the group with rTMS over the ipsilateral M1 compared to the other two groups (Cz and contralateral M1).

Conclusions: Our results support the notion of an interhemispheric competition, and demonstrate the utility of rTMS to explore the functional facilitation of the un-stimulated counterpart M1 with effects on motor execution and learning, which may have implications for neurorehabilitation.
Functional lesions of the motor system with TMS – a challenge for	individual functional mapping
Authors: Lotze M.
Published: December 2019

Applying functional lesions using functional magnetic resonance imaging (fMRI)-navigated transcranial magnetic stimulation (TMS) is a powerful method for investigation of the functional relevance of a given activation site for motor performance in healthy individuals, and also for investigation of the temporal interactions of particular areas during movement preparation. In patients with good cognitive compliance, this procedure may be useful for detection of functional reorganisation or to plan individual therapy directions. Different protocols for applying functional lesions are presented here and their relevance and usage in different applications are explained.
Cortical cellular actions of transcranial magnetic stimulation
Authors: Funke Klaus , Benali Alia
Published: December 2019

Transcranial magnetic stimulation (TMS) can be used in two different ways to manipulate cortical information processing, either by applying a single pulse around the time point of expected task processing or by persistently shifting cortical excitability by repetitive stimulation (rTMS). Single pulses applied when specific cortical processing takes place always impair cortical function due to increased noise or enhanced inhibition, both resulting in decreased signal-to-noise ratio, while repetitive stimulation may allow to weaken or improve cortical processing depending on the type of stimulation. The opposite effects of low- (∼1 Hz) and high-frequency rTMS (5–20 Hz), as well as the opposing effects of continuous versus intermittent theta-burst trains, lowering or raising cortical excitability respectively, have mainly been attributed to synaptic plasticity. As reviewed in this article, in a series of electrophysiological, immunohistochemical and molecular-biological animal experiments we obtained evidence for modulation of inhibitory cortical activity as a further reason of changing cortical excitability following rTMS.
Common networks for selective auditory attention for sounds and words? An fMRI study with implications for attention rehabilitation
Authors: Sturm Walter , Schnitker Ralph , Grande Marion , Huber Walter , Willmes Klaus
Published: December 2019

Purpose: In an fMRI study the functional networks involved in auditory selective attention for sounds and words were investigated. Methods: 24 healthy volunteers (12 male, 12 female) had to respond to a category of targets (animal sounds vs. musical instruments, spoken names of instruments vs. animals; 6 targets, 12 nontargets) presented via headphones. Results: Under both the sound and word condition besides left superior and middle temporal lobe activation there was bilateral activity in the superior frontal (including the anterior cingulate cortex ACC), middle and inferior frontal and inferior parietal lobes. Under both conditions we also found cerebellar activity. In general there was a high overlap of the related attention networks for both conditions. Conclusions: The activation patterns revealed a high overlap across stimulus conditions with only slight modulation caused by the quality of the auditory material. For rehabilitation of attention deficits after brain damage this implicates that a single training procedure might address a common network for selective attention deficits under different stimulus conditions.
Neuroprotective effects of progesterone and allopregnanolone on	long-term cognitive outcome after global cerebral ischemia
Authors: Moralí Gabriela , Montes Pedro , Hernández-Morales Lucía , Monfil Tomás , Espinosa-García Claudia , Cervantes Miguel
Published: December 2019

Purpose: To assess the long-term neuroprotective effects of progesterone (P $_{4}$ ) and allopregnanolone (ALLO) on functional and morphological parameters of the integrity of the hippocampus, after global cerebral ischemia.

Methods: Adult male Sprague-Dawley rats were subjected to a transient severe (20 min) forebrain ischemia (Isch) episode and treated with P $_4$ or ALLO (8 mg/kg i.v.) or its vehicle, at 20 min, 2, 6, 24, 48 and 72 h after ischemia. Rats subjected to Sham procedures, and intact rats were included as non-ischemic controls. Three months after ischemia, both the functional (spatial learning and memory, and reference and working memory), and the morphological integrity (dimensions of the hippocampal formation, thickness of the CA1 subfield, and pyramidal neuron population) of the hippocampus and the medial prefrontal cortex (mPFC) were determined.

Results: Treatment with P $_4$ or ALLO significantly reduced the impairment in spatial learning and memory, as well as in reference and working memory, and prevented the narrowing of the hippocampus, otherwise induced by ischemia. This better performance of P $_4$ - and ALLO-treated rats than vehicle (Veh) -treated rats, occurred in spite of a loss of pyramidal neurons in the CA1, CA2, CA3 and hilus subfields of the Ammon's horn (remaining neurons: Isch+Veh: 21.0, 35.6, 44.1, and 40.3%; Isch+P $_4$ : 19.9, 32.2, 41.1, and 32.5%; Isch+ALLO: 25.5, 62.0, 73.7, and 56.7%), and non-significant changes in the mPFC, as compared to the Intact group (100%).

Conclusions: Performance of P $_4$ - or ALLO-treated rats in learning and memory tests suggests that these steroids promoted neural conditions accounting for adequate functioning long after ischemia, in spite of the loss of hippocampal pyramidal neurons.
Temporal processing as a base for language universals:	Cross-linguistic comparisons on sequencing abilities with some implications for	language therapy
Authors: Szelag Elzbieta , Szymaszek Aneta , Aksamit-Ramotowska Agnieszka , Fink Martina , Ulbrich Pamela , Wittmann Marc , Pöppel Ernst
Published: December 2019

Purposes: The study sets the stage for temporal information processing as a fundamental basis of human cognition and a novel neurorehabilitation method. We focus on auditory perception of temporal order and address the following questions: (1) do subjects' age, gender, hearing status and cognitive functioning influence temporal ordering abilities; (2) are there any differences between Polish and German subjects on these abilities?

Methods: 86 Polish and 82 German subjects aged from 20 to 69 years were classified into 5 age groups. Subjects identified the order of two 1-ms clicks presented monaurally in rapid succession. The temporal order threshold (i.e. the minimum temporal gap required to report the stimulus order at 75% correctness) was assessed for each individual.

Results: There were no differences between Polish and German subjects on temporal ordering. In both samples, a significant prolongation of temporal-order threshold was observed in subjects older than 60 years of age. Temporal processing was relatively resistant to subjects' hearing status, but it depended on cognitive competence. Thus, it is not chronological age as such but cognitive competence that may explain age-related decreases of temporal acuity. Furthermore, potential effects of age or gender are robust against the language background as no differences were observed between Polish and German subjects.

Conclusions: We propose the existence of a neural mechanism underlying the perception of rapid changes in non-verbal acoustic features which constitute a frame for speech perception in many languages. This finding may be important with respect to future applications of temporal training in speech therapy programs designed for patients with receptive language disorders of different etiologies.
Proliferation, migration and differentiation of ependymal region	neural progenitor cells in the brainstem after hypoglossal nerve avulsion
Authors: Fagerlund Michael , Jaff Nasren , Danilov Alexandre I. , Peredo Inti , Brundin Lou , Svensson Mikael
Published: December 2019

Purpose: Cells in the ependymal region in the adult central nervous system (CNS) have been found to possess neural progenitor cell (NPC) like features including capacity for generating new neurons and glia in response to injury and inflammatory disease. Whether these cells are activated after a peripheral nerve injury has not previously been extensively evaluated.

Methods: We investigate the possible activation and effect of NPCs in the ependymal region in the immediate vicinity to the hypoglossal nucleus in the brainstem using two models of injuries, hypoglossal nerve transection and nerve avulsion after which the proliferation, migration and differentiation of ependymal regional NPCs were evaluated.

Results: We showed that: (i) immunoreactivity for Sox2 was detected in cells in the ependymal region of the brainstem and that BrdU/Sox2-positive cells were observed after avulsion, but not after transection injury; (ii) avulsion induces re-expression of nestin in the ependymal layer as well as induced NPC migration from the ependymal layer; (iii) the chemokine SDF-1α (a marker for migrating cells) was upregulated ipsilateral to the nerve injury; (iiii) the NPCs migrating differentiated only into GFAP-positive astrocytes in the hypoglossal nucleus.

Conclusion: These results suggest that nerve avulsion injury induces in parallel with the retrograde "axon reaction" activation of endogenous NPCs in the ependymal region and further suggest that these cells could be involved in repair and neuroregeneration after injury within the brainstem.
Single-session tDCS-supported retraining does not improve fine motor control in musician's dystonia
Authors: Buttkus Franziska , Baur Volker , Jabusch Hans-Christian , de la Cruz Gomez-Pellin Maria , Paulus Walter , Nitsche Michael A. , Altenmüller Eckart
Published: December 2019

Background: Focal dystonia in musicians (MD) is a task-specific movement disorder with a loss of voluntary motor control during instrumental playing. Defective inhibition on different levels of the central nervous system is involved in the pathophysiology. Sensorimotor retraining is a therapeutic approach to MD and aims to establish non-dystonic movements. Transcranial direct current stimulation (tDCS) modulates cortical excitability and alters motor performance. In this study, tDCS of the motor cortex was expected to assist retraining at the instrument. Methods: Nine professional pianists suffering from MD were included in a placebo-controlled double-blinded study. Retraining consisted of slow, voluntarily controlled movements on the piano and was combined with tDCS. Patients were treated with three stimulation protocols: anodal tDCS, cathodal tDCS and placebo stimulation. Results: No beneficial effects of single-session tDCS-supported sensorimotor retraining on fine motor control in pianists with MD were found in all three conditions. Conclusions: The main cause of the negative result of this study may be the short intervention time. One retraining session with a duration of 20 min seems not sufficient to improve symptoms of MD. Additionally, a single tDCS session might not be sufficient to modify sensorimotor learning of a highly skilled task in musicians with dystonia.
Goal-directed visuomotor skill learning: Off-line enhancement and the importance of the primary motor cortex
Authors: Borich Michael , Furlong Mary , Holsman Dennis , Kimberley Teresa Jacobson
Published: December 2019

Purpose: The time course and neural substrates of motor skill learning are not well-understood in healthy or neurologic patient populations. Certain motor skills undergo off-line skill enhancement following training and the primary motor cortex (M1) may be involved. It is unknown if goal-directed visuomotor skill undergoes off-line enhancement or if M1 is associated with that enhancement. Methods: 32 right-handed, healthy subjects were randomly assigned to two groups: real repetitive transcranial magnetic stimulation (rTMS) or sham rTMS applied to the contralateral M1 immediately following one 20-minute finger tracking training session. Tracking performance and cortical excitability were assessed before and after training, following rTMS and 24 hours post-training. Results: Results demonstrate that skill performance continues to develop for at least 30 minutes after training completion, is maintained for 24 hours post-training, and is not affected by inhibitory rTMS applied to M1. Level of skill improvement was associated with the degree of intracortical inhibition increase. Conclusions: These results suggest dispersed information processing for goal-directed visuomotor skill learning following training and a relationship between cortical excitability and skill development in healthy individuals. These findings invite further investigation of the neural mechanisms underlying motor skill learning and may have rehabilitation implications for patients with neurologic injury.
Longitudinal study of wind-up responses after graded spinal cord injuries in the adult rat
Authors: Castro Elena Redondo , Udina Esther , Verdú Enrique , Navarro Xavier
Published: December 2019

Purpose: The main objectives of this work were to evaluate the development of neuropathic pain after spinal cord injuries of different severities, and to assess changes in central excitability and plasticity by means of wind-up responses and withdrawal reflexes. Methods: Two groups of rats were subjected to spinal cord contusion with forces of 100 or 200 kdyn applied at T8. Measurements of thermal and mechanical pain thresholds as well as wind-up measurements were performed weekly during two months after injury. Withdrawal reflexes were also assessed electrophysiologically. Results: We found that animals with contusion of different severities showed a similar reduction in nociceptive thresholds. All contused animals showed increased wind-up responses compared to intact animals during the first 2 to 6 weeks post injury. The mean increase of wind-up was higher in rats with stronger spinal cord contusion. Results from the withdrawal reflexes did not correlate with nociceptive behaviors nor wind-up responses, highlighting the plasticity of spinal circuits modulation after SCI. Conclusion: These results indicate that the graded-force spinal cord contusion model is suitable for studying central neuropathic pain, and for assessing changes in wind-up responses. Wind-up measurements can be used as a non-invasive technique to detect changes in central excitability after SCI of different severities.
Improved picture naming in aphasia patients treated with cathodal tDCS to inhibit the right Broca's homologue area
Authors: Kang Eun Kyoung , Kim Yu Kyeong , Sohn Hae Min , Cohen Leonardo G. , Paik Nam-Jong
Published: December 2019

Purpose: Previous reports have suggested that noninvasive cortical stimulation could influence speech production in patients with chronic stroke. Here, we evaluated the hypothesis that cathodal transcranial DC stimulation (ctDCS), a technique that decreases excitability of stimulated cortical sites, applied over a healthy right Broca's homologue area could improve picture naming in patients with post-stroke aphasia. Methods: Ten right-handed patients with post-stroke aphasia were enrolled in this double blind, counterbalanced sham-controlled, crossover study. Each patient received an intervention of ctDCS (2 mA for 20 min) and of sham tDCS (2 mA for 1 min) daily for 5 consecutive days in a randomized crossover manner with a minimum interval of one week between interventions, over a healthy right Broca's homologue area using a left supraorbital anode and simultaneous daily sessions of conventional word-retrieval training. The primary endpoint measure of this study was a standardized, validated Korean version of the Boston Naming Test, which is a measure of picture naming skills. Results: ctDCS was not found to have any adverse effects. Furthermore, significantly improved picture naming (p = 0.02) was observed at 1 hour following the last (5th) ctDCS treatment session, but no changes were observed after sham tDCS. Conclusion: These results demonstrate that cathodal tDCS over the right healthy Broca's homologue area with a left supraorbital anodal location can improve picture naming task performance in post-stroke aphasia.
Early passage bone marrow stromal cells express genes involved in nervous system development supporting their relevance for neural repair
Authors: Tewarie R.D.S. Nandoe , Bossers K. , Ritfeld G.J. , Blits B. , Grotenhuis J.A. , Verhaagen J. , Oudega M.
Published: December 2019

Purpose: The assessment of the capacity of bone marrow stromal cells (BMSC) to repair the nervous system using gene expression profiling. The evaluation of effects of long-term culturing on the gene expression profile of BMSC. Methods: Fourty four k whole genome rat microarrays were used to study gene expression of cultured BMSC at passage (P)3 and to compare expression profiles between P3 and P14 BMSC. Quantitative PCR was employed to validate the microarray results. Results: P3 BMSC expressed genes involved in neural developmental events such as glial differentiation, neuron proliferation, and neurite formation. They also express genes encoding for growth factors and for proteins involved in growth factor signaling. A total of 6687 genes were co-expressed in P3 and P14 BMSC. Of these co-expressed genes, 3% (202 genes) was differentially expressed with 159 genes higher in P3 BMSC and 43 genes higher in P14 BMSC. The gene expression patterns were independently validated using quantitative PCR. Functional data mining by Gene Ontology (GO)-analysis revealed that 85/159 and 22/43 genes were annotated in the GO database. In P3 BMSC, 53 GO-classes were overrepresented with several involved in organ development, cell proliferation, and neural repair. In P14 BMSC, three GO-classes were overrepresented with one involved in organ development. Conclusions: Our gene profiling results suggested a decreased plasticity and repair aptitude of long-term cultured BMSC. Our data indicated the use of early passage BMSC for neural repair approaches.
Stem cell survival and functional outcome after traumatic brain injury is dependent on transplant timing and location
Authors: Shear Deborah A. , Tate Ciara C. , Tate Matthew C. , Archer David R. , LaPlaca Michelle C. , Stein Donald G. , Dunbar Gary L.
Published: December 2019

Purpose: Recent work indicates that transplanted neural stem cells (NSCs) can survive, migrate to the injury site, and facilitate recovery from traumatic brain injury (TBI). The present study manipulated timing and location of NSC transplants following controlled cortical impact injury (CCI) in mice to determine optimal transplant conditions. Methods: In Experiment 1 (timing), NSCs (E14.5 mouse) were injected into the host striatum, ipsilateral to the injury, at 2, 7, or 14 days. In Experiment 2 (location), NSCs or vehicle were injected into the mouse striatum (7 days post-CCI) either ipsilateral or contralateral to the injury and cognitive and motor abilities were assessed from weeks 1–8 post-transplant. Histological measures of NSC survival, migration, and differentiation were taken at 6 and 8 weeks post-transplant. Results: The results demonstrate that: (1) 2–7 days post-injury is the optimal time-range for delivering NSCs; (2) time of transplantation does not affect short-term phenotypic differentiation; (3) transplant location affects survival, migration, phenotype, and functional efficacy; and (4) NSC-mediated functional recovery is not contingent upon NSC migration or phenotypic differentiation. Conclusions: These findings provide further support for the idea that mechanisms other than the replacement of damaged neurons or glia, such as NSC-induced increases in protective neurotrophic factors, may be responsible for the functional recovery observed in this model of TBI.
Hypoglossal-facial anastomosis (HFA) over a 10 mm gap bridged by a Y-tube-conduit enhances neurite regrowth and reduces collateral axonal branching at the lesion site
Authors: Ozsoy Umut , Demirel Bahadir Murat , Hizay Arzu , Ozsoy Ozlem , Ankerne Janina , Angelova Srebrina , Sarikcioglu Levent , Ucar Yasar , Angelov Doychin N.
Published: December 2019

Purpose: The outcome of severe peripheral nerve injuries requiring surgical repair (transection and suture) is usually poor. Recent work suggests that direct suture of nerves increases collagen production and provides unfavourable conditions for a proper axonal regrowth. We tested whether entubulation of the hypoglossal nerve into a Y-tube conduit connecting it with the zygomatic and buccal facial nerve branches would improve axonal pathfinding at the lesion site, quality of muscle reinnervation and recovery of vibrissal whisking. Methods: For hypoglossal-facial anastomosis (HFA) over a Y-tube (HFA-Y-tube) the proximal stump of the hypoglossal nerve was entubulated and sutured into the long arm of a Y-tube (isogeneic abdominal aorta with its bifurcation). The zygomatic and buccal facial branches were entubulated and sutured to the short arms of the Y-tube. Restoration of vibrissal motor performance, degree of collateral axonal branching at the lesion site and quality of neuro-muscular junction (NMJ) reinnervation were compared to animals receiving HFA-Coaptation (no entubulation) after 4 months. Results: HFA-Y-tube reduced collateral axonal branching. However it failed to reduce the proportion of polyinnervated NMJ and did not improve functional outcome when compared to HFA-Coaptation. Conclusion: Elimination of compression by tightly opposed nerve fragments improved axonal pathfinding. However, biometric analysis of vibrissae movements did not show positive effects suggesting that polyneuronal reinnervation - rather than collateral branching – may be the critical limiting factor. Since polyinnervation of muscle fibers is activity-dependent and can be manipulated, the present findings raise hopes that clinically feasible and effective therapies after HFA could be soon designed and tested.
Coadministration of epidermal growth factor and growth hormone releasing peptide-6 improves clinical recovery in experimental autoimmune encephalitis
Authors: del Barco Diana García , Montero Enrique , Coro-Antich Rosa M. , Brown Enma , Suarez-Alba José , Lopez Laura , Subirós Nelvys , Berlanga Jorge
Published: December 2019

Purpose: Multiple sclerosis is a complex and devastating autoimmune disease of the central nervous system. Up to now, a constellation of candidate drugs have been evaluated with no major success. Experimental Autoimmune Encephalitis (EAE) is the animal counterpart that reproduces critical features of the human MS process. The aim of the present work is to study a possible therapeutic effect of epidermal growth factor (EGF) and growth hormone releasing peptide-6 (GHRP6 coadministration in mild and severe EAE. Methods: Mild and severe forms of EAE were generated immunizing rats and mice with xenogeneic spinal cord homogenate and with the encephalitogenic peptide MOGp35–35, respectively. EGF and GHRP6 alone or combined were administered in therapeutic and prophylactic schedules. A clinical score was established to follow-up the animals during the disease period. Malondialdehyde (MDA) serum concentration and insulin like growth factor-1 (IGF-1) relative level from brain tissue were determined. Results: Only the combined EGF+GHRP6 therapy reduced the clinical score in mild as well in severe EAE forms. The combination also improved the survival rate in nearly 100% of the severe EAE animals. In addition to these effects, there was an increase in the brain IGF-1 transcript and a decrease of serum MDA. Conclusions: EGF+GHRP6 proved to be effective in improving the natural course of both mild and severe EAE. Accordingly, the treatment reduces inflammatory infiltration and microvascular damage, which may be associated to the attenuation of the lipid peroxidation process and the transcriptional enhancement of IGF-1, a major pro-survival factor for brain cells.
Virtual reality based rehabilitation speeds up functional recovery of the upper extremities after stroke: A randomized controlled pilot study in the acute phase of stroke using the Rehabilitation Gaming System
Authors: da Silva Cameirão Mónica , Bermúdez i Badia Sergi , Duarte Esther , Verschure Paul F.M.J.
Published: December 2019

Purpose: Given the incidence of stroke, the need has arisen to consider more self-managed rehabilitation approaches. A promising technology is Virtual Reality (VR). Thus far, however, it is not clear what the benefits of VR systems are when compared to conventional methods. Here we investigated the clinical impact of one such system, the Rehabilitation Gaming System (RGS), on the recovery time course of acute stroke. RGS combines concepts of action execution and observation with an automatic individualization of training. Methods. Acute stroke patients (n = 8) used the RGS during 12 weeks in addition to conventional therapy. A control group (n = 8) performed a time matched alternative treatment, which consisted of intense occupational therapy or non-specific interactive games. Results. At the end of the treatment, between-group comparisons showed that the RGS group displayed significantly improved performance in paretic arm speed that was matched by better performance in the arm subpart of the Fugl-Meyer Assessment Test and the Chedoke Arm and Hand Activity Inventory. In addition, the RGS group presented a significantly faster improvement over time for all the clinical scales during the treatment period. Conclusions. Our results suggest that rehabilitation with the RGS facilitates the functional recovery of the upper extremities and that this system is therefore a promising tool for stroke neurorehabilitation.
Cytoarchitectural characteristics of hippocampal CA1 pyramidal neurons of rats, four months after global cerebral ischemia and progesterone treatment
Authors: Moralí Gabriela , Montes Pedro , González-Burgos Ignacio , Velázquez-Zamora Dulce A. , Cervantes Miguel
Published: December 2019

Purpose: To analyze the cytoarchitectural characteristics of the remaining pyramidal neurons in the hippocampal CA1 subfield of rats, four months after global cerebral ischemia (GCI) and progesterone treatment. Methods: Dendritic arborization, and density and shape of the dendritic spines of CA1 pyramidal neurons in brains of intact rats, or rats submitted 120 days earlier to GCI and treatment with progesterone (8 mg/kg) or its vehicle, at 15 min, and 2, 6, 24, 48, and 72 h after the onset of reperfusion, were analyzed in samples processed by a modified Golgi method. Results: Few impregnated CA1 pyramidal neurons were identified in the ischemic vehicle-treated rats, with a short apical dendrite devoid of bifurcations and dendritic spines. In contrast, the remaining CA1 pyramidal neurons sampled from ischemic progesterone-treated rats showed sinuously branched dendrites with similar number of bifurcations and whole density of spines, and higher proportional density of mushroom spines than those in the intact group. Conclusions: These cytoarchitectural characteristics may underlie the long-term preservation of place learning and memory functions seen after ischemia and progesterone neuroprotective treatment, possibly compensating for the severe reduction in neuronal population.
Excitability changes in the visual cortex quantified with signal detection analysis
Authors: Olma Manuel C. , Kraft Antje , Roehmel Jasper , Irlbacher Kerstin , Brandt Stephan A.
Published: December 2019

Purpose: TDCS can increase excitability in the visual cortex. It is a matter of current debate if tDCS can improve visual performance. Promising parameters to measure detection sensitivity may be those of the signal detection theory ( = SDT), as it allows differentiating between response bias and detection sensitivity changes. The measure of detection sensitivity can be used to predict actual performance under a wide variety of different response criteria. Methods: Here we test if the SDT can quantify tDCS-induced effects in a visual contrast discrimination task in healthy subjects. Results: Anodal stimulation of the visual cortex improved performance, as calculated by detection sensitivity for stimuli presented in the center of the visual field. More peripheral locations in the visual field were unaffected by anodal stimulation. Cathodal stimulation and sham stimulation of the visual cortex had no consistent effect on detection sensitivity. The response bias was not affected by any type of stimulation. Conclusions: Neuroplastic changes in the visual cortex induced by anodal tDCS can be measured by SDT, suggesting SDT could prospectively be a useful approach for monitoring restorative tDCS-effects on visual function in patients with central visual deficits.
4-iodophenyl isothiocyanate: A neuroprotective compound
Authors: Wellejus Anja , Elbrønd-Bek Heidi , Kelly Nicholas M. , Weidner Morten S. , Jørgensen Signe H.
Published: December 2019

Purpose: Naturally occurring isothiocyanates (ITCs) are known to possess chemopreventive and neuroprotective properties. Our objective was to study the synthetic ITC 4-iodophenyl isothiocyanate (4-IPITC) in different models of neurodegeneration. Methods: In vitro, we exposed primary cortical neurons to various insults such as excessive glutamate exposure, oxygen-glucose deprivation, oxidative stress and 1-methyl-phenylpyridinium (MPP+). In vivo, experimental autoimmune encephalomyelitis (EAE) was induced in dark agouti rats treated with 4-IPITC in 3 different concentrations (10, 20 and 40 mg/kg), orally for 28 days. In a Parkinson's model, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was injected in mice pretreated with 4-IPITC (5 mg/kg, orally) for 1 week. Nest building behavior at day 1, 3 and 6 after MPTP injection was assessed along with dopamine and metabolites, and tyrosine hydroxylase (TH) staining on termination day 6. Results: 4-IPITC successfully reduced cell death in all in vitro assays. Moreover, in two independent neurite outgrowth assays the compound showed neurotrophic properties. In the EAE study, 4-IPITC significantly delayed the day of onset and decreased the cumulative EAE score. Although the number of animals in this MPTP study was limited, 4-IPITC showed potential for dampening toxicity. Conclusions: Taken together, our in vitro findings suggest robust neuroprotective and neurotrophic properties of 4-IPITC, which was confirmed in two in vivo models of neurodegeneration.
The impact of rhythm complexity on brain activation during simple singing: An event-related fMRI study
Authors: Jungblut Monika , Huber Walter , Pustelniak Monika , Schnitker Ralph
Published: December 2019

Purpose: Since rhythmical aspects of singing have been neglected up to now our objective was to investigate if it was possible to specify areas concerned with rhythm processing during simple singing. Methods: In an event-related fMRI experiment we tested 30 healthy non-musicians with rhythm sequences, which had to be repeated as monotonously sung vowel changes with (1) regular groupings, (2) regular groupings and rests, and (3) irregular groupings. Results: Common activations for all conditions were found in bilateral supplementary motor area, premotor cortex more distinct in the left hemisphere, left cingulate gyrus, and right basal ganglia. Only irregular groupings making the highest demands on attention, working memory, and sequencing capabilities resulted in additional activation of pars orbitalis and insula more distinct in the left hemisphere, as well as bilateral cingulate gyrus, and parietal lobes. Our analyses demonstrated that bilateral pars orbitalis (BA 47), insula, and left cingulate gyrus are core areas whose activity correlates with rhythm complexity. Conclusions: Rhythm structure is a decisive factor concerning lateralization as well as activation of specific areas during simple singing. This finding suggests a directed use of the singing voice e.g., in order to support language rehabilitation in patients.
FGF1 containing biodegradable device with peripheral nerve grafts induces corticospinal tract regeneration and motor evoked potentials after spinal cord resection
Authors: Nordblom Jonathan , Persson Jonas K.E. , Åberg Jonas , Blom Hans , Engqvist Håkan , Brismar Hjalmar , Sjödahl Johan , Josephson Anna , Frostell Arvid , Thams Sebastian , Brundin Lou , Svensson Mikael , Mattsson Per
Published: December 2019

Purpose: Repairing the spinal cord with peripheral nerve grafts (PNG) and adjuvant acidic fibroblast growth factor (FGF1) has previously resulted in partial functional recovery. To aid microsurgical placement of PNGs, a graft holder device was previously developed by our group. In hope for a translational development we now investigate a new biodegradable graft holder device containing PNGs with or without FGF1. Methods: Rats were subjected to a T11 spinal cord resection with subsequent repair using twelve white-to-grey matter oriented PNGs prepositioned in a biodegradable device with or without slow release of FGF1. Animals were evaluated with BBB-score, electrophysiology and immunohistochemistry including anterograde BDA tracing. Results: Motor evoked potentials (MEP) in the lower limb reappeared at 20 weeks after grafting. MEP responses were further improved in the group treated with adjuvant FGF1. Reappearance of MEPs was paralleled by NF-positive fibers and anterogradely traced corticospinal fibers distal to the injury. BBB-scores improved in repaired animals. Conclusions: The results continue to support that the combination of PNGs and FGF1 may be a regeneration strategy to reinnervate the caudal spinal cord. The new device induced robust MEPs augmented by FGF1, and may be considered for translational research.
Transforming neurorehabilitation of walking following stroke: The promise of non-invasive brain stimulation – a review
Authors: Rogers L.M. , Madhavan S. , Roth H. , Stinear J.W.
Published: December 2019

Purpose: This narrative review discusses the neurophysiology of human motor cortex as it influences gait, and recent advances in the application of non-invasive brain stimulation to the lower limb motor cortex of stroke survivors. Although walking is a high priority following stroke, the efficacy of promising new therapies has yet to warrant their widespread clinical use. For the upper limb, numerous brain stimulation protocols have been described. These protocols, adapted for the leg, are now being used to examine the cortical control of gait. This research discounts the long-held notion that “we walk from our spinal cords”. Methods: Our review describes this research as it relates to the lower limb, especially the use of non-invasive brain stimulation to enhance neuroplasticity. The review also discusses the possible development of a prognostic algorithm for walking recovery after stroke. Conclusion: This review concludes with the expectation that novel brain stimulation protocols combined with therapy will eventually demonstrate a level of effectiveness sufficient to promote their wide acceptance in neurorehabilitation settings.
Changes in white matter integrity follow excitatory rTMS treatment of post-stroke aphasia
Authors: Allendorfer Jane B. , Storrs Judd M. , Szaflarski Jerzy P.
Published: December 2019

Purpose: In this study, we examine whether an excitatory repetitive transcranial magnetic stimulation (rTMS) protocol called intermittent theta burst stimulation (iTBS) applied to the affected left hemisphere leads to changes in white matter fractional anisotropy (FA). Methods: Diffusion tensor imaging (DTI) data were collected in 8 aphasic stroke patients before and after 10 daily iTBS treatments. Alignment of structural and DTI data and derivation of diffusion index maps were performed using Analysis of Functional NeuroImages software followed by Tract-Based Spatial Statistics using FMRIB Software Library. Paired t-tests were performed to compare pre- to post-rTMS changes in FA. Results: There were significant (p < 0.001) left-hemispheric FA increases near the inferior and superior frontal gyri and anterior corpus callosum. FA also increased in the right midbrain and bilaterally near temporal, parietal and posterior cingulate regions. FA decreased bilaterally near the fusiform gyrus and in left cerebellum. Conclusions: Overall, left-hemispheric regions that showed increased FA corresponded to areas previously shown to have increases in fMRI language activation after iTBS. The increased white matter integrity near the stimulation sites may reflect improvements in cortical function mediated by excitatory rTMS through its ability to facilitate synaptic connections.
Administration of cultured autologous bone marrow stromal cells into cerebrospinal fluid in spinal injury patients: A pilot study
Authors: Saito Fukuki , Nakatani Toshio , Iwase Masaaki , Maeda Yuji , Murao Yoshinori , Suzuki Yoshihisa , Fukushima Masanori , Ide Chizuka
Published: December 2019

Purpose: To determine whether intrathecal administration of cultured autologous bone marrow stromal cells (BMSCs) is safe and feasible for treatment of subacute spinal injury. Methods: Five patients with complete tetraplegia due to cervical spinal injury on admission were included. A small amount of bone marrow was obtained during surgery for spinal fusion. BMSCs were cultured, reaching 107–108 cells. The properties and functional efficacy of the BMSCs were verified with surface marker analysis and a neurite extension test. BMSCs were administered by lumbar puncture. The patients were closely observed for 6 months, and the Committee on Effectiveness and Safety of Clinical Treatment (CESCT) evaluated safety. Results: No adverse responses were observed in biochemical and radiographic examinations. The CESCT did not recognize any harmful effects of the transplantation, and concluded it was safe for treatment. The patients were further followed up for 1 to 4 years with no adverse responses. The recovery of American Spinal Injury Association Impairment Scale (AIS) B and C patients at transplantation was rapid and remarkable, but gradual or limited in AIS A patients. Conclusion: This study demonstrated that intrathecal administration of cultured autologous BMSCs is safe and feasible for treatment of spinal cord injury.
Horizontal ladder task-specific re-training in adult rats with contusive thoracic spinal cord injury
Authors: Onifer Stephen M. , Zhang Oliver , Whitnel-Smith Laura K. , Raza Kashif , O'Dell Christopher R. , Lyttle Travis S. , Rabchevsky Alexander G. , Kitzman Patrick H. , Burke Darlene A.
Published: December 2019

Purpose: Using the horizontal ladder task, we examined some issues that need to be resolved before task-specific rehabilitative training can be employed clinically for the frequent contusive spinal cord injury (SCI). We hypothesized that improving recovery in task performance after contusive thoracic SCI requires frequent re-training and initiating the re-training early during spontaneous recovery. Methods: Contusive SCI was produced at the adult female Sprague Dawley rat T10 vertebra. Task re-training was initiated one week later when occasional weight-supported plantar steps were taken overground (n = 8). It consisted of 2 repetitions each day, 5 days each week, for 3 weeks. Task performance and overground locomotion were assessed weekly. Neurotransmission through the SCI ventrolateral funiculus was examined. SCI morphometry was determined. Results: Re-training did not improve task performance recovery compared to untrained Controls (n = 7). Untrained overground locomotion and neurotransmission through the SCI did not change. Lesion area at the injury epicenter as a percentage of the total spinal cord area as well as total tissue, lesion, and spared tissue, white matter, or gray matter volumes did not differ. Conclusions: For the horizontal ladder task after contusive thoracic SCI, earlier re-training sessions with more repetitions and critical neural circuitry may be necessary to engender a rehabilitation effect.
rTMS with motor training modulates cortico-basal ganglia-thalamocortical circuits in stroke patients
Authors: Chang Won Hyuk , Kim Yun-Hee , Yoo Woo-Kyoung , Goo Kyoung-Hyup , Park Chang-hyun , Kim Sung Tae , Pascual-Leone Alvaro
Published: December 2019

Background and purpose: Repetitive transcranial magnetic stimulation (rTMS) may enhance plastic changes in the human cortex and modulation of behavior. However, the underlying neural mechanisms have not been sufficiently investigated. We examined the clinical effects and neural correlates of high-frequency rTMS coupled with motor training in patients with hemiparesis after stroke. Methods: Twenty-one patients were randomly divided into two groups, and received either real or sham rTMS. Ten daily sessions of 1,000 pulses of real or sham rTMS were applied at 10 Hz over the primary motor cortex of the affected hemisphere, coupled with sequential finger motor training of the paretic hand. Functional MRIs were obtained before and after training using sequential finger motor tasks, and performances were assessed. Results: Following rTMS intervention, movement accuracy of sequential finger motor tasks showed significantly greater improvement in the real group than in the sham group (p < 0.05). Real rTMS modulated areas of brain activation during performance of motor tasks with a significant interaction effect in the sensorimotor cortex, thalamus, and caudate nucleus. Patients in the real rTMS group also showed significantly enhanced activation in the affected hemisphere compared to the sham rTMS group. Conclusion: According to these results, a 10 day course of high-frequency rTMS coupled with motor training improved motor performance through modulation of activities in the cortico-basal ganglia-thalamocortical circuits.