Frontiers in Neurology

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ISSN / EISSN : 1664-2295 / 1664-2295
Published by: Frontiers Media SA (10.3389)
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Published: 13 July 2021
Frontiers in Neurology, Volume 12; doi:10.3389/fneur.2021.716308

Abstract:
Editorial on the Research Topic Glial Dysfunction in Epileptogenesis Epilepsy is one of the most common neurological disorders affecting around 1% of the world's population (1). Epilepsy research has so far mainly focused on how to inhibit epileptic discharges resulting in different symptomatic treatment options targeted at neurons. Despite the introduction of more than 20 novel anti-seizure medications since the early 1990s, the proportion of people with drug-refractory epilepsy has remained notably stable at ~30% (2). Given the expanding spectrum of important functions ascribed to the non-neuronal constituents of the brain, we can now observe a paradigm shift where glial cells are included in the equation of epilepsy pathogenesis. With our novel understanding of glial cells as central organizers of homeostatic functions and as major contributors to inflammation and brain excitability, we are approaching novel curative treatment strategies for epilepsy. In the future, targeting dysfunctional and/or reactive glia or glia-mediated inflammatory processes may thus prevent initiation and progression of epilepsy, and yield true anti-epileptogenic medications. In this special issue (SI) of Frontiers in Neurology, we brought together experts in this new area of epilepsy research, and provide a balanced collection of seven original studies and eight review articles. The eBook both starts and ends with reviews of one of the core homeostatic functions of astrocytes, which is glutamate handling in the central nervous system. Glutamate clearance is highly relevant for epilepsy pathogenesis as excess glutamate directly could trigger neuronal discharges and epileptic activity. The first article, presented by Peterson and Binder (USA), provides a systematic overview of the functional components of astrocyte glutamate control. Astrocytes express both glutamate transporters (GLT-1 and GLAST in rodents/EAAT 1 and 2 in humans), as well as metabotropic glutamate receptors (mGluR)3 and mGluR5. Peterson and Binder demonstrate evidence for dysregulation of these channels across patients with epilepsy and preclinical seizure models. After uptake, astrocytes conduct the intracellular metabolization of glutamate and ammonia to glutamine. Sandhu et al. from the group of Tore Eid (USA) highlight the importance of the enzyme glutamine synthetase (GS), and provide evidence for the association of astrocytic GS deficiency or dysfunction in discrete brain regions in several types of epilepsy, including mesial temporal lobe epilepsy, neocortical epilepsies, and glioblastoma-associated epilepsy. These findings are reinforced by several studies using experimental inhibition or deletion of GS in specific brain regions, and by this mimic different human epilepsy forms including their comorbidities. Alcoreza et al. from the group of Harald Sontheimer (USA) provide information on astrocytic glutamate receptor dysregulation in epilepsy, presenting yet another view of the delicate regulatory processes of glutamate homeostasis. They also highlight the importance of extracellular space volume alterations and dysregulation of the water channel aquaporin-4 as integral parts of epilepsy pathophysiology and discuss evidence for upregulation of system x–c, a cystine/glutamate antiporter expressed by astrocytes in epileptic tissue. Kinboshi et al. (Japan) focuses on another important homeostatic function of astrocytes, which is K+ spatial buffering. This process mainly depends on inwardly rectifying potassium (Kir) 4.1 channels and gap junction coupling. Astrocytes rapidly transport K+ from areas of high neuronal activity, where [K+]EC increases, to regions with lower K+ levels via the astrocyte network through gap junctions. This K+ clearance mechanism is not only critical for maintaining K+ homeostasis and preventing neural hyperexcitability but is also linked to glutamate uptake during normal brain function. There is ample evidence for Kir4.1 dysfunction in epilepsy and recent studies indicate that inhibition of Kir4.1 channels facilitates the expression of brain-derived neurotrophic factor (BDNF), an important modulator of epileptogenesis in astrocytes. Verhoog et al. from the group of Erwin van Vliet (The Netherlands) enriches this eBook with a substantial review of state-of-the-art literature on dysfunctional astrocytes in epilepsy, also including the role astrocyte Ca2+ signaling, altered blood brain barrier (BBB) function and blood flow regulation. The series of contributions to this eBook on glia-derived inflammation in epilepsy could not have a better opening than with an original study on febrile seizures, provided by Brennan et al. from the group of Tallie Baram (USA). The potential role of aberrant microglia and astrocyte function during epileptogenesis is important because the involved mediators provide targets for intervention and prevention of epilepsy. By performing experimental febrile status epilepticus in rat pups, the authors elicited a strong inflammatory response leading to a rapid and sustained upregulation of pro-inflammatory cytokines. In the attempt to curb epileptogenesis, several pathways involving cytokines, microRNAs, high mobility group B-1 (HMGB1) and prostaglandin E2 signaling were targeted by using network-specific interventions as well as global anti-inflammatory approaches. The failure of selectively decreasing the expression of downstream inflammatory cascades, and the emergence of intolerable side effects, illustrates that the intricate, cell-specific and homeostatic interplays among these networks constitute a serious challenge to tailored interventions that aim to prevent epileptogenesis. Another approach to curb epileptogenesis is presented in the study of Wyatt-Johnson et al. (USA). Microglial survival and proliferation are regulated by the colony-stimulating factor 1 receptor (CSF1R). The authors used the CSF1R inhibitor PLX3397 in a rat pilocarpine model of status epilepticus (SE)....
Corrigendum
, Paula Montesinos, Alicia Alonso-Jiménez, Jorge Alonso-Pérez, David Reyes-Leiva, Javier Sánchez-González, Jaume Llauger-Roselló, Sonia Segovia, Izaskun Belmonte, Irene Pedrosa, et al.
Published: 13 July 2021
Frontiers in Neurology, Volume 12; doi:10.3389/fneur.2021.727020

Abstract:
A Corrigendum on Magnetization Transfer Ratio in Lower Limbs of Late Onset Pompe Patients Correlates With Intramuscular Fat Fraction and Muscle Function Tests by Nuñez-Peralta C, Montesinos P, Alonso-Jiménez A, Alonso-Pérez J, Reyes-Leiva D, Sánchez-González J, et al. (2021). Front. Neurol. 12:634766. doi: 10.3389/fneur.2021.634766 In the published article, there was an error regarding the affiliation(s) for Claudia Nuñez-Peralta. As well as having affiliation(s) ** 1 **, they should also have **2Departament de Medicina, Universidad Autónoma de Barcelona, Barcelona, Spain**. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated. Keywords: late onset Pompe disease, lower limb muscle, magnetic transfer ratio, intramuscular fat fraction, muscle function tests Citation: Nuñez-Peralta C, Montesinos P, Alonso-Jiménez A, Alonso-Pérez J, Reyes-Leiva D, Sánchez-González J, Llauger-Roselló J, Segovia S, Belmonte I, Pedrosa I, Martínez-Noguera A, Matellini-Mosca B, Walter G and Díaz-Manera J (2021) Corrigendum: Magnetization Transfer Ratio in Lower Limbs of Late Onset Pompe Patients Correlates With Intramuscular Fat Fraction and Muscle Function Tests. Front. Neurol. 12:727020. doi: 10.3389/fneur.2021.727020 Received: 17 June 2021; Accepted: 18 June 2021; Published: 13 July 2021. Approved by: Copyright © 2021 Nuñez-Peralta, Montesinos, Alonso-Jiménez, Alonso-Pérez, Reyes-Leiva, Sánchez-González, Llauger-Roselló, Segovia, Belmonte, Pedrosa, Martínez-Noguera, Matellini-Mosca, Walter and Díaz-Manera. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Claudia Nuñez-Peralta, [email protected]; Jordi Díaz-Manera, [email protected]
Na Xu, Li-Xia Li, Tian-Long Wang, Li-Qun Jiao, Yang Hua, Dong-Xu Yao, Jie Wu, Yan-Hui Ma, Tian Tian, Xue-Li Sun
Published: 12 July 2021
Frontiers in Neurology, Volume 12; doi:10.3389/fneur.2021.666814

Abstract:
Background: Patients undergoing carotid endarterectomy (CEA) for severe carotid stenosis are vulnerable to postoperative delirium, a complication frequently associated with poor outcome. This study investigated the impact of processed electroencephalogram (EEG)-guided anesthesia management on the incidence of postoperative delirium in patients undergoing CEA. Methods: This single-center, prospective, randomized clinical trial on 255 patients receiving CEA under general anesthesia compared the outcomes of patient state index (PSI) monitoring [SEDLine Brain Function Monitor (Masimo, Inc, Irvine, CA)] (standard group, n = 128) with PSI combined with density spectral array(DSA) -guided monitoring (intervention group, n = 127) to reduce the risk of intraoperative EEG burst suppression. All patients were monitored by continuous transcranial Doppler ultrasound (TCD) and near-infrared spectroscopy (NIRS) to avoid perioperative cerebral hypoperfusion or hyperperfusion. According to the surgical process, EEG suppression time was calculated separately for three stages: S1 (from anesthesia induction to carotid artery clamping), S2 (from clamping to declamping), and S3 (from declamping to the end of surgery). The primary outcome was incidence of postoperative delirium according to the Confusion Assessment Method algorithm during the first 3 days post-surgery, and secondary outcomes were other neurologic complications and length of hospital stay. Results: There were no episodes of cerebral hypoperfusion or hyperperfusion according to TCD and NIRS monitoring in either group during surgery. The incidence of postoperative delirium within 3 days post-surgery was significantly lower in the intervention group than the standard group (7.87 vs. 28.91%, P < 0.01). In the intervention group, the total EEG suppression time and the EEG suppression time during S2 and S3 were shorter (Total, 0 “0” vs. 0 “1.17” min, P = 0.04; S2, 0 “0” vs. 0 “0.1” min, P < 0.01; S3, 0 “0” vs. 0 “0” min, P = 0.02). There were no group differences in incidence of neurologic complications and length of postoperative hospital stay. Conclusion: Processed electroencephalogram-guided general anesthesia management, consisting of PSI combined with DSA monitoring, can significantly reduce the risk of postoperative delirium in patients undergoing CEA. Patients, especially those exhibiting hemodynamic fluctuations or receiving surgical procedures that disrupt cerebral perfusion, may benefit from the monitoring of multiple EEG parameters during surgery. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03622515.
Rongrong Zhang, Hui Wei, Yu Ren, Yanping Wu, Yetao Luo, Lei Zhang, Yingchao Huo, Jinzhou Feng, Philippe P. Monnier,
Published: 12 July 2021
Frontiers in Neurology, Volume 12; doi:10.3389/fneur.2021.685454

Abstract:
Background: Intravenous thrombolysis with alteplase benefits eligible patients with acute ischemic stroke. However, in some countries such as China, alteplase may be too expensive for low-income patients, and also for regions with low economic development. Urokinase is much less expensive than alteplase. This study aimed to assess the outcomes and treatment complications of urokinase in acute ischemic stroke patients, which are poorly understood. Methods: This multicenter retrospective study included acute ischemic stroke patients who received intravenous urokinase or alteplase from January 2014 to January 2018 at 21 centers in China. Outcomes and treatment complications were analyzed by univariate and multivariate analyses. Results: Among the 618 patients included in this study, 489 were treated with urokinase and 129 were treated with alteplase. Functional independence, no/minimal disability, mortality, intracranial hemorrhage (ICH), and symptomatic ICH did not significantly differ between the urokinase and alteplase groups in the univariate and multivariate analyses. However, the patients who received alteplase had a lower odds ratio (OR) of extracranial bleeding in the univariate analysis and a lower adjusted OR (aOR) in the multivariate analysis than the patients who received urokinase (OR = 0.410 [95% CI, 0.172–0.977], p = 0.038; aOR = 0.350 [95% CI, 0.144–0.854], p = 0.021). Furthermore, in patients treated with urokinase, the patients who received high-dose urokinase had a higher OR of extracranial bleeding in the univariate analysis and a higher aOR of extracranial bleeding in the multivariate analysis than patients who received low-dose urokinase (OR = 3.046 [95% CI, 1.696–5.470], p < 0.001; aOR = 3.074 [95% CI, 1.627–5.807], p = 0.001). Moreover, patients who received low-dose urokinase had similar outcomes and complications compared to patients treated with alteplase. Conclusions: Patients treated with urokinase had similar outcomes but a higher risk of extracranial bleeding compared to patients treated with alteplase. The risk of extracranial bleeding was higher in the patients treated with high-dose urokinase than in the patients treated with low-dose urokinase. Patients who received low-dose urokinase had similar outcomes and complications compared to patients treated with alteplase. In countries such as China where some acute ischemic stroke patients cannot afford alteplase, urokinase may be a good alternative to alteplase for intravenous thrombolysis.
Yusong Pei, Zhihua Xu, Guobiao Liang, Hai Jin, , Benqiang Yang, Xinxin Qiao, Hongrui You, Dengxiang Xing
Published: 12 July 2021
Frontiers in Neurology, Volume 12; doi:10.3389/fneur.2021.693549

Abstract:
Background: This study was conducted to explore the risk factors of anterior circulation intracranial aneurysm rupture based on extracranial carotid artery (ECA) tortuosity. Methods: This retrospective study, conducted from January 1, 2017, to March 1, 2021, collected and reviewed the clinical and imaging data of 308 patients with anterior circulation intracranial aneurysm [133 (43.2%) patients in the ruptured aneurysm group; 175 (56.8%) patients in the unruptured aneurysm group]. Computed tomography angiography (CTA) of the head and neck was used to determine the ECA tortuosity (normal, simple tortuosity, kink, coil) and the morphologic parameters of the aneurysms. The relationship of aneurysm rupture to ECA tortuosity and the morphologic parameters were analyzed. Results: After univariate analysis, kink, angle of flow inflow (FA), aspect ratio (AR), aneurysm length (L), the distance from the tortuosity to the aneurysm (distance), and size ratio (SR) were significantly correlated with anterior circulation intracranial aneurysm rupture (p < 0.05). Spearman correlation analysis showed that ECA tortuosity was correlated with FA and SR (p < 0.05). Multiple logistic analyses showed that FA [odds ratio (OR), 1.013; 95% CI, 1.002–1.025], SR (OR, 1.521; 95% CI, 1.054–2.195), and kink (OR, 1.823; 95% CI, 1.074–3.096) were independently associated with aneurysm rupture. Conclusion: Study results suggest that FA, SR, and ECA kink were independent risk factors associated with anterior circulation intracranial aneurysm rupture.
Rose-Angélique Belot, Margaux Bouteloup, , Anne-Laure Parmentier, Eloi Magnin, Frédéric Mauny, Fabrice Vuillier
Published: 12 July 2021
Frontiers in Neurology, Volume 12; doi:10.3389/fneur.2021.706639

Abstract:
Objectives: The aim of this observational study was to describe social support and patterns of attachment among patients with migraine. We hypothesized that in comparison to the general population, insecure attachment is overrepresented in migraine patients, and that these patients have less social support. We also aimed to study the specific relationship between attachment and social support. We hypothesized that patients with an insecure attachment style have less social support than patients with a secure attachment style. Methods: A total of 101 consecutive patients (88.1% women) aged between 25 and 60 (average age = 41.4) were recruited at the Specialized Center for the Consultation of Primary Headaches at the Regional University Hospital Center of Besançon (France). Migraine impact and disability were evaluated using the Headache Impact Test (HIT-6) questionnaire and Migraine Disability Assessment (MIDAS) questionnaire. Patients also completed several self-administered psychological questionnaires in their validated French versions: the Medical Outcome Survey 36-Item Short-Form Health Survey, the Cungi Scale, the State-Trait Anxiety Inventory, the Beck Depression Inventory, the Relationship Scales Questionnaire and the Sarason's Social Support Questionnaire. Results: The distribution of attachment profiles was different from that of the general population, with an overrepresentation of insecure attachment styles (p = 0.018). Our study showed that migraine patients had less social support than the general population, both in terms of the number of people providing support (p = 0.002) and the level of satisfaction concerning this social support (p = 0.000). We also found that neither the number of available persons score nor the satisfaction score were statistically different between the four attachment categories (p = 0.49). Patient's attachment style and social support influence the patient-doctor relationship, the therapeutic alliance and health behaviors such as treatment adherence. Conclusions: Based on the data we obtained, we developed applications in patient care for people with particular attachment styles and low social support. A treatment plan adapted to the patient's attachment profile should be created to develop “precision medicine” using a personalized approach to the doctor-patient relationship. We would also recommend encouraging patients to participate in support groups, in order to strengthen their attachment systems and gain social support. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03577548, identifier NCT03577548.
Karen Tse, Edward Beamer, Deborah Simpson, Robert J. Beynon, Graeme J. Sills, Thimmasettappa Thippeswamy
Published: 12 July 2021
Frontiers in Neurology, Volume 12; doi:10.3389/fneur.2021.625017

Abstract:
Intracranial electroencephalography (EEG) is commonly used to study epileptogenesis and epilepsy in experimental models. Chronic gliosis and neurodegeneration at the injury site are known to be associated with surgically implanted electrodes in both humans and experimental models. Currently, however, there are no reports on the impact of intracerebral electrodes on proteins in the hippocampus and proinflammatory cytokines in the cerebral cortex and plasma in experimental models. We used an unbiased, label-free proteomics approach to identify the altered proteins in the hippocampus, and multiplex assay for cytokines in the cerebral cortex and plasma of C57BL/6J mice following bilateral surgical implantation of electrodes into the cerebral hemispheres. Seven days following surgery, a repeated low dose kainate (KA) regimen was followed to induce status epilepticus (SE). Surgical implantation of electrodes reduced the amount of KA necessary to induce SE by 50%, compared with mice without surgery. Tissues were harvested 7 days post-SE (i.e., 14 days post-surgery) and compared with vehicle-treated mice. Proteomic profiling showed more proteins (103, 6.8% of all proteins identified) with significantly changed expression (p < 0.01) driven by surgery than by KA treatment itself without surgery (27, 1.8% of all proteins identified). Further, electrode implantation approximately doubled the number of KA-induced changes in protein expression (55, 3.6% of all identified proteins). Further analysis revealed that intracerebral electrodes and KA altered the expression of proteins associated with epileptogenesis such as inflammation (C1q system), neurodegeneration (cystatin-C, galectin-1, cathepsin B, heat-shock protein 25), blood–brain barrier dysfunction (fibrinogen-α, serum albumin, α2 macroglobulin), and gliosis (vimentin, GFAP, filamin-A). The multiplex assay revealed a significant increase in key cytokines such as TNFα, IL-1β, IL-4, IL-5, IL-6, IL-10, IL12p70, IFN-γ, and KC/GRO in the cerebral cortex and some in the plasma in the surgery group. Overall, these findings demonstrate that surgical implantation of depth electrodes alters some of the molecules that may have a role in epileptogenesis in experimental models.
Neha Singh, Megha Saini, Nand Kumar, M. V. Padma Srivastava, S. Senthil Kumaran,
Published: 12 July 2021
Frontiers in Neurology, Volume 12; doi:10.3389/fneur.2021.680733

Abstract:
Background: In this study, a novel electromechanical robotic exoskeleton was developed for the rehabilitation of distal joints. The objective was to explore the functional MRI and the neurophysiological changes in cortical-excitability in response to exoskeleton training for a 9-year chronic stroke patient. Case-Report: The study involved a 52-year old female patient with a 9-year chronic stroke of the right hemisphere, who underwent 20 therapy sessions of 45 min each. Cortical-excitability and clinical-scales: Fugl-Mayer (FM), Modified Ashworth Scale (MAS), Brunnstrom-Stage (BS), Barthel-Index (BI), Range of Motion (ROM), were assessed pre-and post-therapy to quantitatively assess the motor recovery. Clinical Rehabilitation Impact: Increase in FM wrist/hand by 6, BI by 10, and decrease in MAS by 1 were reported. Ipsilesional Motor Evoked Potential (MEP) (obtained using Transcranial Magnetic Stimulation) was increased by 98 μV with a decrease in RMT by 6% and contralesional MEP was increased by 43 μV with a decrease in RMT by 4%. Laterality Index of Sensorimotor Cortex (SMC) reduced in precentral- gyrus (from 0.152 to −0.707) and in postcentral-gyrus (from 0.203 to −0.632). Conclusion: The novel exoskeleton-based training showed improved motor outcomes, cortical excitability, and neuronal activation. The research encourages the further investigation of the potential of exoskeleton training.
Przemysław Podgórski, Marta Waliszewska-Prosół, Anna Zimny, Marek Sąsiadek,
Published: 12 July 2021
Frontiers in Neurology, Volume 12; doi:10.3389/fneur.2021.645974

Abstract:
Introduction: Age-related brain changes are one of the most important world health problems due to the rising lifespan and size of the elderly populations. The aim of the study was to assess the effect of ageing in women on coordinated brain activity between eight resting-state networks. Material and Methods: The study group comprised 60 healthy female volunteers who were divided into two age groups: younger women (aged 20–30 n = 30) and older women (aged 55–80 n = 30). Resting-state data were collected during a 15 min scan in the eyes-closed condition using a 3T MR scanner. Data were preprocessed and analysed using the CONN toolbox version 19.c. The large-scale network analysis included a priori selected regions of interest of the default mode, the sensorimotor, the visual, the salience, the dorsal attention, the fronto-parietal, the language, and the cerebellar network. Results: Within the visual, the default mode, the salience, and the sensorimotor network, the intra-network resting-state functional connectivity (RSFC) was significantly higher with increasing age. There was also a significant increase in the inter-network RSFC in older females compared to young females found in the following networks: sensorimotor lateral and salience, salience and language, salience and fronto-parietal, cerebellar anterior and default mode, cerebellar posterior and default mode, visual and sensorimotor lateral, visual and sensorimotor, visual lateral and default mode, language and cerebellar anterior, language and cerebellar posterior, fronto-parietal and cerebellar anterior, dorsal attention and sensorimotor, dorsal attention and default mode, sensorimotor superior, and salience. Compared to young females, elderly women presented bilaterally significantly lower inter-network RSFC of the salience supramarginal gyrus and cerebellar posterior, sensorimotor lateral, and cerebellar anterior network, and sensorimotor lateral and cerebellar posterior as well as sensorimotor superior and cerebellar posterior network. Conclusion: Increased RSFC between some brain networks including the visual, the default mode, the salience, the sensorimotor, the language, the fronto-parietal, the dorsal attention, and the cerebellar networks in elderly females may function as a compensation mechanism during the ageing process of the brain. To the best of our knowledge, this study is the first to report the importance of increase of cerebellar networks RSFC during healthy female ageing.
, Margaret M. Shields, Melissa R. Meister, Gregory Murtha, Brian P. Curry, Bradley A. Dengler
Published: 12 July 2021
Frontiers in Neurology, Volume 12; doi:10.3389/fneur.2021.685313

Abstract:
Traumatic brain injury is a rapidly increasing source of morbidity and mortality across the world. As such, the evaluation and management of traumatic brain injuries ranging from mild to severe are under active investigation. Over the last two decades, quantitative pupillometry has been increasingly found to be useful in both the immediate evaluation and ongoing management of traumatic brain injured patients. Given these findings and the portability and ease of use of modern pupillometers, further adoption and deployment of quantitative pupillometers into the preclinical and hospital settings of both resource rich and medically austere environments.
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