bluuebunny/crossref_metadata_2025 huggingface dataset:
Different effects of the mirror illusion on motor and somatosensory processing
Authors: Fritzsch Claire , Wang Jing , dos Santos Luara Ferreira , Mauritz Karl-Heinz , Brunetti Maddalena , Dohle Christian
Published: December 2019

Purpose: Mirror therapy can improve motor and sensory functions, but effects of the mirror illusion on primary motor and somatosensory cortex could not be established consistently. Methods: Fifteen right handed healthy volunteers performed or observed a finger-thumb opposition task. Cerebral activations during normal movement (NOR), mirrored movement (MIR) and movement observation (OBS) by means of a video chain were recorded with functional magnetic resonance imaging (fMRI). Activation sizes in movement > static conditions were identified using SPM8 (p < 0.001, unc.) and attributed to predefined areas employing the Anatomy toolbox 1.8. Laterality indices for the responsive areas were calculated on the basis of the number of activated voxels. Results: Relevant bilateral BOLD responses were found in primary motor (M1) and somatosensory (S1 – BA 2, 3b and 3a) cortex, premotor and parietal areas and V5. When comparing MIR to NOR, no significant change of contralateral activation in M1 was found, but clearly at S1 with differences between hands. Conclusion: The mirror illusion does not elicit immediate changes in motor areas, yet there is a direct effect on somatosensory areas, especially for left hand movements. These results suggest different effects of mirror therapy on processing and rehabilitation of motor and sensory function.
Core stabilization exercise with real-time feedback for chronic hemiparetic stroke: A pilot randomized controlled trials
Authors: Chung Eunjung , Lee Byoung-Hee , Hwang Sujin
Published: December 2019

Objective: The purpose of this study was to examine the feasibility of core stabilization exercise with real-time feedback on balance and gait function in patients with chronic hemiparetic stroke. Methods: Nineteen stroke subjects were enrolled in this study. The patients were randomly divided into the experimental (n = 10) and control groups (n = 9). Subjects in the experimental group performed core stabilization exercise with real-time feedback training for 30 minutes per day during a period of six weeks. Subjects in the control group performed core stabilization exercise during the same period. This study assessed the kinematic parameters using a portable walkway system, and timed up-and-go test. Results: Gait velocity showed significantly greater improvement in the experimental group (7.3 ± 5.0 sec) than in the control group (−0.7 ± 10.6). Stride length showed significantly greater increase in the experimental group (13.2 ± 7.9 on the affected side and 12.6 ± 8.0 on the less affected side) than the control group (3.5 ± 8.7 on the affected side and 3.4 ± 8.5 on the less affected side). After training, change in results on the timed up and go test was significantly greater in the experimental group than in the control group. Conclusion: Core stabilization exercise using real-time feedback produces greater improvement in gait performance in chronic hemiparetic stroke patients than core stabilization exercise only.
Serial treatments of primed low-frequency rTMS in stroke: Characteristics of responders vs. nonresponders
Authors: Carey James R. , Deng Huiqiong , Gillick Bernadette T. , Cassidy Jessica M. , Anderson David C. , Zhang Lei , Thomas William
Published: December 2019

Purpose: This study analyzed the characteristics of responders vs. nonresponders in people with stroke receiving a novel form of repetitive transcranial magnetic stimulation (rTMS) to improve hand function. Methods: Twelve people with stroke received five treatments of 6-Hz primed low-frequency rTMS to the contralesional primary motor area. We compared demographic factors, clinical features, and the ipsilesional/contralesional volume ratio of selected brain regions in those who improved hand performance (N = 7) on the single-hand component of the Test Évaluant la performance des Membres supérieurs des Personnes Âgées (TEMPA) and those who showed no improvement (N = 5). Results: Responders showed significantly greater baseline paretic hand function on the TEMPA, greater preservation volume of the ipsilesional posterior limb of the internal capsule (PLIC), and lower scores (i.e. less depression) on the Beck Depression Inventory than nonresponders. There were no differences in age, sex, stroke duration, paretic side, stroke hemisphere, baseline resting motor threshold for ipsilesional primary motor area (M1), NIH Stroke Scale, Upper Extremity Fugl-Meyer, Mini-Mental State Examination, or preservation volume of M1, primary somatosensory area, premotor cortex, or supplementary motor area. Conclusion: Our results support that preserved PLIC volume is an important influential factor affecting responsiveness to rTMS.
Cognitive and brain reserve for mind-body therapeutic approaches in multiple sclerosis: A review
Authors: Crescentini Cristiano , Urgesi Cosimo , Fabbro Franco , Eleopra Roberto
Published: December 2019

Purpose: Cognitive impairment is one of the most disabling symptoms of multiple sclerosis (MS), affecting a large proportion of patients and having a severe impact on their quality of life. Nevertheless, there exists a large variability in the neuropsychological profiles of MS patients and some of them appear to withstand better than others the MS-related brain pathology before showing cognitive decline. In recent years, many studies have made use of concepts such as cognitive reserve and brain reserve to take account of the inter-individual discrepancy between cognitive impairment and MS pathology. Critically, these studies have left open the fundamental issue of the clinical implications of this research for the treatment of cognitive dysfunction in MS. Methods and Results: We provide an updated and extensive overview of the studies that have explored cognitive and brain reserve in MS and discuss their implications for non-pharmacological therapeutic strategies aimed at potentiating patients' reserve. In particular, the possible utility of integrated approaches based on mind-body techniques such as mindfulness-meditation is considered. Conclusions: We conclude that these techniques represent challenging mental enriching activities that may help cultivating cognitive reserve and more systematic research on their efficacy to protect against cognitive degradation in MS is encouraged.
Freezing of gait in Parkinson's disease: Current treatments and the potential role for cognitive training
Authors: Walton Courtney C. , Shine James M. , Mowszowski Loren , Naismith Sharon L. , Lewis Simon J. G.
Published: December 2019

Freezing of gait (FOG) is a complex motor symptom of Parkinson's disease that manifests as an inability to generate effective gait, leading to a significant falls risk and a severe impact on quality of life. Research into effective treatment options has provided relatively limited benefits and is often hindered by substantial limitations. In this article, current treatment and research options are briefly discussed and a proposal for the further exploration of non-invasive therapeutic approaches is given. Recent advances in the literature continue to identify a pattern of selective executive dysfunction in patients with freezing of gait and such findings highlight a possible common underlying pathophysiology. Therefore, cognitive training is of particular interest as it may be able to improve executive processes thus reducing the manifestation of FOG. This article focuses on the existing evidence for such intervention strategies and proposes that targeted cognitive training may offer a novel treatment option for FOG that is worthy of an increased research focus.
Forced limb-use enhances brain plasticity through the cAMP/PKA/CREB signal transduction pathway after stroke in adult rats
Authors: Qu Huiling , Zhao Mei , Zhao Shanshan , Xiao Ting , Tang Xiaoyu , Zhao Dongjiao , Jolkkonen Jukka , Zhao Chuansheng
Published: December 2019

Purpose: The mechanism underlying forced limb-use -induced structural plasticity remains to be studied. We examined whether the cyclic adenosine monophosphate (cAMP)–mediated signal transduction pathway was involved in brain plasticity and promoted behavioral recovery induced by forced limb-use after stroke. Methods: Adult rats were divided into a sham group, an ischemia group, an ischemia group with forced limb-use, and an ischemia group with forced limb-use and infusion of N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide (H89). Forced limb-use began on post-stroke day 7. Biotinylated dextran amine (BDA) was injected into the sensorimotor cortex on post-stroke day 14. Behavioral recovery was evaluated on post-stroke days 29 to 32, and the levels of cAMP, PKA C-α, phosphorylated CREB (pCREB), synaptophysin, PSD-95, BDA, and BrdU/NeuN were measured. Results: The number of midline-crossing axons and the expression levels of synaptophysin and PSD-95 were increased after forced limb-use. Forced limb-use enhanced the survival of the newborn neurons and increased the levels of cAMP, PKA C-α and pCREB. These were significantly suppressed by H89. Behavioral performance improved with forced limb-use and was reversed with H89. Conclusions: Enhanced structural plasticity and the behavioral recovery promoted by post-stroke forced limb-use are suggested to be mediated through the cAMP/PKA/CREB signal transduction pathway.
Learning, memory and brain plasticity in posttraumatic stress disorder: Context matters
Authors: Flor Herta , Nees Frauke
Published: December 2019

We review evidence from our laboratory that suggests that in addition to enhanced cue conditioning and delayed cue extinction disturbed contextual learning may play an important role in the development and maintenance of posttraumatic stress disorder. Based on data from a longitudinal sample of rescue workers at high risk for posttraumatic stress disorder and data on single trauma exposed persons with and without posttraumatic stress disorder we show the crucial role of the hippocampus for contextual memory and impaired contextual learning along with enhanced cue conditioning and delayed extinction in PTSD. Using structural and functional magnetic resonance imaging we confirmed animal data on the role of the hippocampus in contextual and the importance of the amygdala in cue conditioning and the role of the frontal cortex in extinction. Genetic variants related to the modulation of the hypothalamus-pituitary-adrenal axis are associated with cue and genetic variants related to calcium signaling and memory processes and the regulation of the stress response are associated with context conditioning. These genes also play a role in PTSD. Further research needs to identify the predictive nature of these learning processes and plastic brain changes and their interaction with genetic characteristics changes for the transition into PTSD and its maintenance. A further focus needs to be on the identification of learning and memory mechanisms and the associated brain plasticity across disorders.
Neuroimaging and plasticity in schizophrenia
Authors: Meyer-Lindenberg Andreas , Tost Heike
Published: December 2019

Schizophrenia is a frequent and highly heritable brain disorder that typically manifests around or after puberty and has a fluctuating course. Multiple lines of evidence point to a neurodevelopmental origin of the illness and suggest that its (post) pubertal manifestation is related to genetic and environmental risk factors that interfere with the structural and functional reorganization of neural networks at this time. Longitudinal structural neuroimaging studies point to a progressive reduction in gray matter volume in many brain regions in schizophrenia. It has been proposed that these neuroimaging observations reflect an enduring disturbance of experience-dependent synaptic plasticity arising from developmental abnormalities in key neural circuits implicated in schizophrenia, including dorsolateral prefrontal cortex and hippocampal formation. Recent work has identified genetic variants linked to neural plasticity that are associated with changes in these circuits. Furthermore, non-invasive interventions such as transcranial magnetic stimulation have been shown to impact some of these systems-level intermediate phenotypes, suggesting a modifiability of these core pathophysiological processes of schizophrenia that may be exploited by therapy.
Anodal transcranial direct current stimulation over the dorsolateral prefrontal cortex improves anorexia nervosa: A pilot study
Authors: Khedr Eman M. , Elfetoh Noha Abo , Ali Anwer M. , Noamany Mostafa
Published: December 2019

Background: Existing treatments for adults with anorexia nervosa (AN) have limited proven efficacy. New treatments that have been suggested involve targeted, brain-directed interventions such as transcranial direct current stimulation (tDCS). We describe findings from seven individuals with treatment-resistant AN who received 10 sessions of anodal tDCS, over the left dorsolateral prefrontal cortex (DLPFC). Material and method: In this open-label, single-arm study, seven patients received anodal tDCS (2mA) for 25 minutes over the left dorsolateral prefrontal cortex daily for ten days. Assessments pre-tDCS, post-tDCS and one month later included the Eating Attitude Test (EAT), Eating Disorder Inventory (EDI) and Beck Depression Inventory (BDI). Results: Three patients improved in all three rating scales immediately after the treatment sessions and one month later. Two patients showed improvement at the end of treatment but returned to the baseline after one month. One subject improved only on the BDI scale but not eating scales. The scores in the three rating scales were unaffected by treatment in the remaining patient. There was a significant effect of time (pre, post and 1 month later) on the three rating scores; BDI (P = 0.016), EDI (P = 0.018) and EAT (P = 0.016) and a significant correlation between the percent improvement of BDI and EAT (p = 0.01), and between BDI and EDI (P = 0.006). Conclusions: These findings suggest that tDCS has potential as an adjuvant treatment for AN and deserves further study.
Visual improvement and pain resolution in traumatic optic nerve sheath meningocele treated by optic nerve sheath fenestration
Authors: Hui Chen , Xiaoyun Wu , Yi Liang , Ningbo Chen , Xizhong Qiu , Shaowei Yang , Wei Lin , Maozhu Zhao , Wubo Ma , Xuefei Pan , Li Lai , Haibin Tan , Daiwen Zeng , Yong Jiang
Published: December 2019

Purpose: There is no consensus as to the optimum treatment for traumatic optic neuropathy (TON). The decision to intervene medically or surgically, or simply observe was recommended to be on an individual basis. The purpose of this study is to test whether optic nerve sheath fenestration (ONSF) could improve vision in patients with traumatic optic nerve sheath meningocele, although it was reported to be effective in patients with traumatic optic nerve sheath hematoma. Methods: ONSF was performed on two traumatic patients with dilated optic nerve sheath from MRI. Results: Both patients initially suspected as traumatic optic nerve sheath hematoma were diagnosed as traumatic optic nerve sheath meningocele by intraoperative findings of the enlarged optic nerve sheath and clear fluid drained without evidence of blood in the subdural space. Moreover, significant orbit/head pain resolution and visual improvement within a week after ONSF was found. Conclusions: When TON presents with an enlarged optic nerve/sheath on CT or MRI with visual loss, an optic nerve sheath meningocele should be considered with the consideration that ONSF may benefit both visual acuity and post-traumatic pain, if present.
Contingent capture of involuntary visual spatial attention does not differ between normally hearing children and proficient cochlear implant users
Authors: Kamke Marc R. , Van Luyn Jeanette , Constantinescu Gabriella , Harris Jill
Published: December 2019

Purpose: Evidence suggests that deafness-induced changes in visual perception, cognition and attention may compensate for a hearing loss. Such alterations, however, may also negatively influence adaptation to a cochlear implant. This study investigated whether involuntary attentional capture by salient visual stimuli is altered in children who use a cochlear implant. Methods: Thirteen experienced implant users (aged 8–16 years) and age-matched normally hearing children were presented with a rapid sequence of simultaneous visual and auditory events. Participants were tasked with detecting numbers presented in a specified color and identifying a change in the tonal frequency whilst ignoring irrelevant visual distractors. Results: Compared to visual distractors that did not possess the target-defining characteristic, target-colored distractors were associated with a decrement in visual performance (response time and accuracy), demonstrating a contingent capture of involuntary attention. Visual distractors did not, however, impair auditory task performance. Importantly, detection performance for the visual and auditory targets did not differ between the groups. Conclusion: These results suggest that proficient cochlear implant users demonstrate normal capture of visuospatial attention by stimuli that match top-down control settings.
Age at stroke determines post-stroke language lateralization
Authors: Szaflarski J.P. , Allendorfer J.B. , Byars A.W. , Vannest J. , Dietz A. , Hernando K.A. , Holland S.K.
Published: December 2019

Purpose: To determine how age at the time of left middle cerebral artery stroke affects language lateralization in a combined sample of subjects with perinatal, childhood, and adult stroke. Methods: 19 participants who had perinatal stroke (<1 month of age), 32 with later stroke, and 51 sex-/age-matched healthy controls (HCs) received fMRI of language using verb generation task (VGT). Results: Percent lesion volumes were not different between groups (perinatal vs. late stroke) when taking brain volume into account (p = 0.084). Perinatal stroke group showed bilateral signal increases compared to more left-lateralized signals in matched HCs; late stroke group and HCs both showed left-hemispheric signal increases. LIs in the stroke groups were consistently more bilateral than in HCs (all p < 0.008) except for the late group's posterior LI (p = 0.080). There was greater proportion of leftward language lateralization in HCs compared to their respective stroke groups (78.9% vs. 31.6% in perinatal; 87.5% vs. 59.4% in late stroke; p = 0.004) and a larger proportion of leftward lateralization in late compared to perinatal stroke (p = 0.039). The age of stroke occurrence showed significant positive associations with global and frontal LI (both p ≤ 0.007). Conclusion: As expected, the age of stroke occurrence affects subsequent verb generation lateralization. Greater cortical plasticity is observed in earlier stroke while later stroke is associated with reliance on the repair of the previously damaged left-hemispheric networks.
Neural plasticity of voice processing: Evidence from event-related potentials in late-onset blind and sighted individuals
Authors: Föcker Julia , Hölig Cordula , Best Anna , Röder Brigitte
Published: December 2019

Purpose: Intra- and crossmodal neuroplasticity have been reported to underlie superior voice processing skills in congenitally blind individuals. The present study used event-related potentials (ERPs) in order to test if such compensatory plasticity is limited to the developing brain. Methods: Late blind individuals were compared to sighted controls in their ability to identify human voices. A priming paradigm was employed in which two successive voices (S1, S2) of the same (person-congruent) or different speakers (person-incongruent) were presented. Participants made an old-young decision on the S2. Results: In both groups ERPs to the auditory S2 were more negative in person-incongruent than in person-congruent trials between 200–300 ms. A topographic analysis suggested a more posteriorly shifted distribution of the Person Match effect (person-incongruent minus person-congruent trials) in late blind individuals compared to sighted controls. Conclusion: In contrast to congenitally blind individuals, late blind individuals did not show an early Person Match effect in the time range of the N1, suggesting that crossmodal compensation is mediated by later processing steps rather than by changes at early perceptual levels.
Combining enriched environment and induced pluripotent stem cell therapy results in improved cognitive and motor function following traumatic brain injury
Authors: Dunkerson Jacob , Moritz Kasey E. , Young Jennica , Pionk Tim , Fink Kyle , Rossignol Julien , Dunbar Gary , Smith Jeffrey S.
Published: December 2019

Purpose: Despite advances towards potential clinically viable therapies there has been only limited success in improving functional recovery following traumatic brain injury (TBI). In rats, exposure to an enriched environment (EE) improves learning and fosters motor skill development. Induced pluripotent stem cells (iPSC) have been shown to survive transplantation and influence the recovery process. The current study evaluated EE and iPSC as a polytherapy for remediating cognitive deficits following medial frontal cortex (mFC) controlled cortical impact (CCI) injury. Methods: Sixty adult male rats received a midline mFC CCI or sham injury and were randomly placed in either EE or standard environment (SE). Seven days post-injury rats received bilateral transplantation of iPSCs or media. Behavioral measures were conducted throughout the remainder of the study. Following behavioral analysis, brains were extracted and prepared for histological analysis. Results: Open-field data revealed that combined therapy resulted in typical Sham/EE activity rearing patterns by the conclusion of the study. On the Vermicelli Handling task, rats with EE/iPSC polytherapy performed better than media-treated rats. Furthermore, rats treated with polytherapy performed equivalently to Sham/EE rats on the Morris water maze. Proficiency on the Rotarod was consistently better in EE when compared to SE counterparts. Confocal microscopy confirmed that iPSCs survived and migrated away from the transplantation site. Conclusions: Overall, EE or iPSC therapy improved cognition and motor performance, however, full cognitive restoration was seen only with the EE/iPSC treatment. These data suggest that EE/iPSC therapy should be explored as a potential, clinically relevant, treatment for TBI.
Functional protection of learning and memory abilities in rats with vascular dementia
Authors: Yang Huiyun , Shi Ouyan , Jin Yanjiao , Henrich-Noack Petra , Qiao Haixuan , Cai Chunquan , Tao Huaying , Tian Xin
Published: December 2019

Purpose: The present study clarified the effects of repetitive transcranial magnetic stimulation (rTMS) in rats with vascular dementia (VaD) and explored the underlying mechanisms. Methods: Two-vessel occlusion was used as a VaD model. Two weeks after carotid artery occlusion, high (5 Hz) or low (1 Hz) frequency rTMS were applied for 10 days. Spatial learning and memory abilities were tested with a Morris water maze. Hippocampal CA1 neurons were histologically examined. The expressions of mammalian target of rapamycin (mTOR) and eukaryotic initiation factor 4E (eIF-4E) in CA1 were detected by western blot, and immunohistochemistry. Results: Unlike unlesioned control animals, VaD rats had an impaired morphology of CA1 neurons and a reduced ability of spatial memory. rTMS significantly improved both, the morphology and the learning and memory abilities of VaD rats compared to untreated lesioned rats. Protein expressions of mTOR and eIF-4E in CA1 of VaD rats were lower than in control rats but rTMS significantly increased the expression compared to untreated VaD rats. Conclusions: rTMS promotes recovery of learning and memory abilities of VaD rats. Molecular analysis suggests that the beneficial effect of rTMS may be partly induced by upregulation of protein expressions of mTOR and eIF-4E in CA1.
Do all sub acute stroke patients benefit from robot-assisted therapy? A retrospective study
Authors: Duret Christophe , Hutin Emilie , Lehenaff Laurent , Gracies Jean-Michel
Published: December 2019

Purpose: Upper limb robot-assisted rehabilitation is a highly intensive therapy, mainly recommended after stroke. Whether robotic therapy is suitable for subacute patients with severe impairments including cognitive disorders is unknown. This retrospective study explored factors impacting on motor performance achieved in a 16-session robotic training combined with standard rehabilitation. Methods: Seventeen subacute inpatients (age 53 ± 18; 49 ± 26 days post-stroke) were assessed at baseline using upper extremity motor impairments scales, Functional Independence Measure, aphasia and neglect scores. Number of movements and robotic assistance were compared between Session 2 (S2), 8 (8) and 16 (S16), Motricity Index between pre and post-treatment. Correlation analyses explored predictors of motor performance. Results: Overall, number of movements and Motricity Index increased significantly while robot-assistance decreased. The mean number of movements per session correlated positively with baseline motor capacities but not with age, aphasia and neglect. However, the increase in Motricity index correlated negatively with baseline Motricity index and the increase in the number of movements correlated negatively with the number of movements at S2. Conclusion: High intensity robot-assisted training may be associated with motor improvement in subacute hemiparesis. More severely impaired patients may derive greater benefit from robot-assisted training; age, aphasia and neglect do not represent exclusion criteria.
Evaluation of differences in brain neurophysiology and morphometry associated with hand function in individuals with chronic stroke
Authors: Borich Michael R. , Neva Jason L. , Boyd Lara A.
Published: December 2019

Purpose: Rehabilitation interventions need to be optimized to maximize therapeutic effects and minimize stroke-related disability. However, a comprehensive understanding of the neural substrates underlying recovery is lacking. The purpose of this study was to investigate relationships between brain anatomy, physiology and hand motor function in individuals with chronic stroke. Methods: Transcranial magnetic stimulation (TMS) and magnetic resonance imaging (MRI) approaches were used to evaluate cortical excitability and brain structural morphometry in individuals with chronic stroke. Hemispheric differences and relationships between these measures and hand dexterity were evaluated. Results: Hemispheric differences were observed for TMS and MRI measures. Bilateral hand dexterity correlated with TMS resting motor threshold and precentral gyral thickness. Transcallosal inhibition across hemispheres was positively associated with midcallosal white matter volume. Regression modeling results demonstrated that combining TMS and MRI measures predicted unique amounts of variance in hand dexterity. Conclusions: Results confirm and extend findings showing differences in brain structure and function after stroke. Results suggested a structure-function relationship underlying interhemispheric connectivity in chronic stroke. The utility of combined TMS and MRI measures to predict motor function can be used in future investigations to aid identifying optimal biomarkers of stroke recovery to predict response to rehabilitation to maximize treatment outcomes.
A case of post-traumatic minimally conscious state reversed by midazolam: Clinical aspects and neurophysiological correlates
Authors: Carboncini Maria Chiara , Piarulli Andrea , Virgillito Alessandra , Arrighi Pieranna , Andre Paolo , Tomaiuolo Francesco , Frisoli Antonio , Bergamasco Massimo , Rossi Bruno , Bonfiglio Luca
Published: December 2019

Purpose: We describe the case of a subject in a post-traumatic Minimally Conscious State (MCS) who retrieved full interaction with the environment after midazolam infusion. We studied EEG correlates of the “awakening reaction” in the different domains of frequency, time and cortical topography, along with the intrinsic connectivity within both the task-positive and the linguistic network. Methods: EEG recorded before and after midazolam administration has been submitted to spectral power analysis, sLORETA analysis and intrinsic connectivity analysis within both functional networks. Results: A critical change in the power spectrum profile was observed after midazolam: a) the power between 1 and 12 Hz decreased, reaching its maximum difference with respect to pre-infusion at about 7 Hz and b) the power between 12 and 30 Hz increased, with a maximum difference at about 15 Hz. At the same time, midazolam induced significant connectivity changes, especially for these two frequency bands, within both functional networks. Conclusions: We advance some hypotheses about certain aspects of the recovery from the MCS both in terms of anatomo-functional correlations and functional brain systems and we make inferences about the role that some kind of ‘catatonic’ symptoms might play in determining and/or maintaining this peculiar clinical state.
Tissue culture studies of neural plasticity
Authors: Seil Fredrick J.
Published: December 2019

Exposure of cerebellar cultures derived from neonatal mice to cytosine arabinoside for the first 5 days in vitro results in destruction of cerebellar granule cells and inhibition of glial maturation. Such cultures undergo reorganizational changes, primary features of which are a sprouting of Purkinje cell recurrent axon collaterals and the formation of recurrent axon collateral-Purkinje cell dendritic spine synapses. Such heterotypical synapses are inhibitory, in contrast to the excitatory parallel fiber-Purkinje cell dendritic spine synapses normally present. If locus coeruleus neurons are included with the cerebellar cultures, the catecholaminergic axons also sprout, and tissue levels of catecholamines are increased. Purkinje cell survival is enhanced in Ara C-treated cultures, as the target field for Purkinje cell axonal projections is expanded. Oligodendrocyte inhibition results in failure of myelination, and astrocyte inhibition, when it occurs, is associated with a failure of Purkinje cell ensheathment and a hypennnervation of Purkinje cell somata by sprouted recurrent axon collateral terminals. Transplantation of such cultures with granule cells and glia reverses many of these changes. Parallel fiber-Purkinje cell dendritic spine synapses are formed, and most heterotypical synapses disappear. The Purkinje cell population is reduced to normal, and most of the sprouted recurrent axon collaterals are eliminated. However, sprouted catecholaminergic axons are not significantly reduced. Transplanted cultures become myelinated and Purkinje cells acquire astrocytic sheaths, with an associated reduction of axosomatic synapses. Transplantation with glia alone does not reduce the sprouted recurrent axon collaterals, but does result in astrocytic ensheathment of Purkinje cells and an associated decrease of axosomatic synapses. These tissue culture models illustrate some of the plastic changes that the nervous system may undergo following injury and transplantation.
Fetal neocortical transplants grafted into cortical lesion cavities made in newborn rats receive multiple host afferents. A retrograde fluorescent tracer analysis
Authors: Castro A.J. , Sørensen J.C. , Tønder N. , Bold L. , Zimmer J.
Published: December 2019

Several reports have demonstrated efferent projections from fetal neocortical transplants placed in the cerebral cortex of newborn rats. Fewer studies have examined transplant afferents, and these have primarily used techniques based on the axonal transport of horseradish peroxidase. In the present study, we extend these initial findings on transplant afferent connections by using retrogradely transported fluorescent dyes to demonstrate a topographic and more extensive pattern of cortical transplant afferents than has been previously reported. Fetal neocortical tissue was grafted into frontal cortical lesion cavities made by aspiration in newborn rats. At 1.5–10 months later, the fluorescent dyes Fast blue and Diamidino yellow were injected into the transplants. Subsequent histological analysis demonstrated numerous retrogradely labeled fluorescent neurons within the host thalamus and cerebral cortex as well as several other areas of the host brain. The neurons were primarily single-labeled and generally found in areas that normally project to the ablated area of the cortex. The topographic distribution of retrograde labeling in several animals with non-overlapping dye injections confined to the transplants suggests that the host projections were distributed selectively within the grafts. These results support and extend previous studies suggesting the use of fetal neocortical tissue in repair of the neonatally damaged central nervous system.
Expression of growth-associated proteins (GAPs) in injured sensory axons of frogs acclimatized to 15 °C and 25 °C
Authors: Bisby M.A. , Redshaw J.D. , Tetzlaff W. , de Leon M. , Carlsen R.C.
Published: December 2019

Labelled proteins conveyed by fast axonal transport into the sensory axons of frog sciatic nerve following axotomy have been studied by 2D gel electrophoresis. Previous work showed that in frogs acclimatized to 25 °C a cell body reaction occurs, along with regeneration of axons to their targets. In contrast, frogs acclimatized to 15 °C showed no cell body reaction and though regeneration began, it stalled after approximately 35 days. We found that axotomy at 25 °C was followed by an increase in transport of specific labelled proteins corresponding to growth-associated proteins (GAPs) identified in other regenerating systems. Surprisingly, axotomy at 15 °C also induced a similar increase, though with a slower onset, so that the highest levels of expression of GAPs occurred during the time when the axons had stalled. We conclude that sensory neurons in 15 °C frogs do detect that their axons have been injured, as shown by their ability to increase GAP synthesis. Slow and limited axonal growth is possible during a period when GAP synthesis is low compared to levels in rapidly regenerating nerves, but even when the ability to produce GAPs increases, this alone is not sufficient to sustain regeneration in the absence of other components of the cell body reaction to injury.
Rabbit retinal ganglion cells survive optic nerve transection and entubulation repair with type I collagen nerve guide tubes
Authors: Rosario Carlos M. , Fry Keith R. , Madison Roger
Published: December 2019

The major objective of the experiments reported in this paper was to qualitatively test the hypothesis that rabbit retinal ganglion cells survive optic nerve transection and entubulation repair of the proximal optic nerve stump. The optic nerve of rabbits was transected immediately behind the globe, and a 1-cm length of a Type I collagen nerve guide tube was sutured onto the short proximal stump. The nerve guide was either left empty or was filled with a Type I collagen gel (Vitrogen, Collagen Corp.). Following 8–12 weeks survival time, the animals were sacrificed and the retinae were prepared as whole mounts and processed for immunocytochemistry using an antibody which selectively labels the retinal ganglion cells. Although no formal cell counts were carried out, the animals which received Vitrogen within the nerve guide showed a qualitative enhancement of retinal ganglion cell survival compared to the group with the nerve guide alone. The results suggest that specific manipulations of the central nervous system microenvironment may enhance neuronal survival following axonal transection.
Comparison of the synthesis and axonal transport of fucosylated glycoproteins by intact and regenerating sensory neurons in the frog
Authors: De Leon Marino , Carlsen Richard C.
Published: December 2019

Peripheral nerve regeneration requires a reorganization of neuronal synthesis and axonal transport to replace the degenerating axon. This study examines the time course, the extent and the molecular components which comprise the observed increases in protein fucosylation and fast axonal transport of fucosylated proteins in regenerating frog peripheral nerves. The in vitro spinal ganglia-sciatic nerve preparation used in these experiments allowed comparisons to be made between axotomized and intact neurons from the same animal, incubated in the same [3H]fucose-containing solution, and subjected to the same axonal transport conditions. Thus, we were able to show that the fucosylation of constituent proteins increased in axotomized neurons without an increase in the membrane transport of fucose or neuronal protein synthesis. An increase in the amount of newly fucosylated protein conveyed by fast transport preceded the apparent increase in neuronal synthesis by approximately 3 days. The increase in anterograde transport was initiated just subsequent to a transient increase in retrograde or ‘turnaround’ transport, suggesting a possible association between the two responses. The protein (distinguished on the basis of molecular weight) undergoing the most pronounced increase in fucosylation in the cell body was different from that in the nerve, but there was no evidence for the production of novel glycoproteins. The data indicate that protein fucosylation increases significantly in regenerating neurons and that an increase in the incorporation of newly fucosylated protein into the fast axonal transport system precedes an increase in synthesis. The increase in transport of fucosylated protein may be one of the earliest responses directed toward the generation of a new axon.
Alteration of cytoskeletal organization during axonal elongation and its role in regulating the growth process
Authors: Cancalon Paul F.
Published: December 2019

The composition and organization of the axonal cytoskeleton vary from neuron to neuron and the ability of a nerve to regenerate may, at least in part, depend on the pre-existing nature of the cytoskeleton. In axons, where the cytoskeletal elements are loosely organized enough material may be mobilized after an injury to allow elongation to proceed. However, if microtubules and neurofilaments interact closely with each other, it may not be possible for enough material to be released from or to migrate through a complex network. As a consequence material is not provided to the growing tip and elongation cannot proceed beyond the initial sprouting.
Cytoskeletal protein synthesis and regulation of nerve regeneration in PNS and CNS neurons of the rat
Authors: Tetzlaff W. , Bisby M.A.
Published: December 2019

Following injury to the facial nerve, facial motoneurons respond with a rapid suppression of neurofilament synthesis, and an increase in actin and tubulin synthesis. In situ hybridization studies show that these changes are the result of alterations in levels of the corresponding mRNAs. The increased ratio of neurofilament to tubulin expression is also characteristic of developing neurons, and direct evidence for the idea that axon injury provokes a partial return to a developmental state is provided by the finding that there is rapid re-expression of a developmentally regulated α-tubulin gene. In magnocellular rubrospinal neurons, whose axons do not regenerate after injury, the same initial changes in gene expression occurred, but they were not sustained. We do not know whether this is cause or effect of the failure to regenerate, but we can conclude that injured CNS neurons have the potential to respond to injury by initiating a ‘regeneration programme’. Failure to sustain this programme is presumably due to differences in the trophic environment of central and peripheral axons.
Increase in protein and tubulin mRNA synthesis in frog sensory neurons treated with the adenylate cyclase activator, forskolin
Authors: Carlsen Richard C. , De Leon Marino , Tetzlaff Wolfram , Parhad Irma M. , Bisby Mark A.
Published: December 2019

We are interested in the role cyclic AMP may play as a mediator of growth factor-induced gene expression in regenerating peripheral nerves. As a first step, we investigated mRNA levels and protein synthesis in intact frog dorsal root ganglia (DRG) treated with the adenylate cyclase activator, forskolin in vitro. Forskolin (10−7 M) increased intraganglionic cyclic AMP concentration 3-fold within 40 min of application and maintained this concentration through 60 min, when the drug was withdrawn. Addition of forskolin to isolated DRG neurons for 1 h increased the incorporation of [3H]leucine into TCA-insoluble material beginning 12 h after the withdrawal of forskolin. Axonally transported labeled material was increased almost 2-fold by 12 h. The effect of forskolin could be blocked by the simultaneous addition of actinomycin D, but not if actinomycin D was added 1 h later. Northern and dot-blot analysis of RNA extracted from the treated ganglia indicated that an mRNA coding for an α-subunit of tubulin was increased by treatment with forskolin. 2D PAGE also demonstrated an increase in an α-subunit of tubulin. An increase in neuronal cyclic AMP appears to selectively increase the production of specific proteins and may contribute to the production of macromolecules involved in the initiation and stimulation of axonal regeneration.
Effects of human growth hormone on peripheral nerve regeneration
Authors: Skottner Anna , Kanje Martin , Arrhenius-Nyberg Vibeke , Lundborg Göran
Published: December 2019

Systemic administration of human growth hormone (hGH) to intact or hypophysectomized rats was found to stimulate regeneration of the crush-lesioned sciatic nerve. The IGF-I levels of serum of the treated rats did not correlate with regeneration of the nerve but hGH treatment increased the IGF-I content of the nerve. The results suggest that a GH-mediated increase of IGF-I in the sciatic nerve could be involved in the stimulatory effect of GH on neurite outgrowth.
Posttranslational modification of nerve proteins by amino acids
Authors: Ingoglia N.A. , Chakraborty G. , Yu M. , Luo D. , Liu C.
Published: December 2019

Both axonal and glial components of nerve are capable of carrying out reactions in which Arg, Lys, Leu, Pro, Val, AJa and Ser can be covalently linked to endogenous proteins in reactions which require tRNA but occur in the absence of ribosomes and ribosomal RNA. These posttranslational protein modifications appear to play important roles in nerve regeneration since they are increased more than 10-fold within 2 h of a crush injury in nerves which are capable of regeneration, but are not activated in nerves not capable of regrowth following injury. The regulation of the modification of proteins by Arg and Lys in vivo appears to be the function of separate peptides. The exogenous application of serine protease inhibitors (but not other protease inhibitors) mimics the effect of the endogenous peptides, suggesting that the endogenous regulators have serine protease inhibitory activity. The targets for modification are proteins of low abundance and thus far have been identified only in terms of their molecular weights and isoelectric points. The site of addition of Arg, but not the other amino acids, to target proteins is to the amino terminus. The addition of Arg to an amino terminus is likely to be involved in the ubiquitin mediated proteolysis of the modified protein. One of the most unusual findings in these series of experiments is that in regenerating sciatic nerves, amino acid modified proteins aggregate to form complexes of greater than 2 × 106 Da. The significance of this finding is not known. But we speculate that the aggregate may result from the assembly of an insoluble functional unit of the cell from soluble precursor proteins, and that the trigger for their assembly is amino acid modification.
The behavioral and anatomical effects of prenatal umbilical cord clamping in the rat and their alteration by the prior maternal administration of nimodipine
Authors: Shen Yong , Isaacson Robert L. , Smotherman William P.
Published: December 2019

This study investigated the effects of fetal rat umbilical cord compression on anatomical, biochemical, and behavioral parameters of development. Further, the study examined the ability of the calcium channel antagonist nimodipine to afford protection from this insult. Near the day of birth (E21), the umbilical cord of individual fetuses was not clamped or clamped for 2, 6, or 12 min. Before clamping, mothers were given 70 μg/kg (i.p.) nimodipine in a polyethylene glycol (PEG) vehicle or the vehicle alone. Selected animals were sacrificed for cytochrome oxidase histochemistry. The remainder of the pups were given to foster mothers and allowed to develop through adulthood. At the end of testing all animals were sacrificed and the brains weighed and measured. Histochemical analysis revealed that clamping resulted in a decrease in cytochrome oxidase reaction product in the hippocampus. The reduction in this marker of oxidative metabolism was not as pronounced in animals from drug-treated mothers. Alterations in behavior produced by clamping were detectable as early as the third day after birth (P3). At this age, pups subjected to cord clamping exhibited impaired righting and diminished avoidance of a ‘cliff’ on which they had been placed. On P67–P75, clamped animals exhibited hyperactivity in an open field, low rates of spontaneous alternation in a T-maze, and impaired learning and memory in a Pavlovian conditioned aversion-to-brightness test. The calcium channel blocker afforded protection from the effects of cord clamping, since the nimodipine-treated animals were less impaired in these behavioral tests. Animals that had been subjected to cord clamping showed reduced brain volumes and dimensions on P80. Nimodipine treatment normalized these parameters of brain development relative to non-clamped controls. Taken together, these results indicate that brief periods of umbilical cord occlusion near the time of birth can have both immediate and long-term effects on different parameters of development. In addition, the calcium channel blocker nimodipine affords partial protection from damage induced by compression of the fetal umbilical cord.
Substantia nigra grafts and Parkinson's disease: from animal experiments to human therapeutic trials
Authors: Freed William J.
Published: December 2019

During the decade since the first reports of functional effects of substantia nigra (SN) transplantation in animal models of Parkinson's disease, the procedure has progressed to human clinical trials. There is evidence that SN grafts can produce some alleviation of the manifestations of SN lesions in animal models, and by several measures these grafts appear to function in a manner similar to the normal SN. There do, however, appear to be limitations on the efficacy of SN allografts in rodent models, that may be related to an inability of fetal SN transplants to fully integrate into the host brain structure. No method of overcoming this limitation has yet been found. Studies of transplantation of human fetal SN to immunosuppressed rat hosts suggest that human donor tissue exerts proportionately greater effects than rat tissue, and is similarly effective when transplanted as solid tissue fragments or as dissociated cells. Only recently, a few controlled studies have obtained evidence for positive effects of SN grafts in primate models of Parkinson's disease. In the few clinical studies reported thus far, there are indications that some clinical improvements can be produced by SN grafts, although there is little or no evidence that the clinical changes found so far are larger than the changes that have been seen after adrenal medulla grafts. The possibility of a role of striatal injury in the clinical changes has not been resolved. It is noteworthy that nearly all of the studies of SN transplantation in rodents, primates, and humans have employed methodologies similar to those developed in the course of the first few reports on SN transplantation, and that the effects obtained by these methods are limited, even in rats. The possibility is raised that fundamental advances in SN transplantation techniques may be important for the development of a more efficacious clinical procedure.