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Brain Sci., Volume 3, Issue 2 (June 2013), Pages 415-1012

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Research

Jump to: Review, Other

Open AccessArticle Compensating for Language Deficits in Amnesia II: H.M.’s Spared versus Impaired Encoding Categories
Brain Sci. 2013, 3(2), 415-459; doi:10.3390/brainsci3020415
Received: 20 December 2012 / Revised: 17 March 2013 / Accepted: 19 March 2013 / Published: 27 March 2013
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Abstract
Although amnesic H.M. typically could not recall where or when he met someone, he could recall their topics of conversation after long interference-filled delays, suggesting impaired encoding for some categories of novel events but not others. Similarly, H.M. successfully encoded into internal representations
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Although amnesic H.M. typically could not recall where or when he met someone, he could recall their topics of conversation after long interference-filled delays, suggesting impaired encoding for some categories of novel events but not others. Similarly, H.M. successfully encoded into internal representations (sentence plans) some novel linguistic structures but not others in the present language production studies. For example, on the Test of Language Competence (TLC), H.M. produced uncorrected errors when encoding a wide range of novel linguistic structures, e.g., violating reliably more gender constraints than memory-normal controls when encoding referent-noun, pronoun-antecedent, and referent-pronoun anaphora, as when he erroneously and without correction used the gender-inappropriate pronoun “her” to refer to a man. In contrast, H.M. never violated corresponding referent-gender constraints for proper names, suggesting that his mechanisms for encoding proper name gender-agreement were intact. However, H.M. produced no more dysfluencies, off-topic comments, false starts, neologisms, or word and phonological sequencing errors than controls on the TLC. Present results suggest that: (a) frontal mechanisms for retrieving and sequencing word, phrase, and phonological categories are intact in H.M., unlike in category-specific aphasia; (b) encoding mechanisms in the hippocampal region are category-specific rather than item-specific, applying to, e.g., proper names rather than words; (c) H.M.’s category-specific mechanisms for encoding referents into words, phrases, and propositions are impaired, with the exception of referent gender, person, and number for encoding proper names; and (d) H.M. overuses his intact proper name encoding mechanisms to compensate for his impaired mechanisms for encoding other functionally equivalent linguistic information. Full article
Open AccessArticle Sex-Specific Brain Deficits in Auditory Processing in an Animal Model of Cocaine-Related Schizophrenic Disorders
Brain Sci. 2013, 3(2), 504-520; doi:10.3390/brainsci3020504
Received: 23 January 2013 / Revised: 4 March 2013 / Accepted: 20 March 2013 / Published: 10 April 2013
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Abstract
Cocaine is a psychostimulant in the pharmacological class of drugs called Local Anesthetics. Interestingly, cocaine is the only drug in this class that has a chemical formula comprised of a tropane ring and is, moreover, addictive. The correlation between tropane and addiction is
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Cocaine is a psychostimulant in the pharmacological class of drugs called Local Anesthetics. Interestingly, cocaine is the only drug in this class that has a chemical formula comprised of a tropane ring and is, moreover, addictive. The correlation between tropane and addiction is well-studied. Another well-studied correlation is that between psychosis induced by cocaine and that psychosis endogenously present in the schizophrenic patient. Indeed, both of these psychoses exhibit much the same behavioral as well as neurochemical properties across species. Therefore, in order to study the link between schizophrenia and cocaine addiction, we used a behavioral paradigm called Acoustic Startle. We used this acoustic startle paradigm in female versus male Sprague-Dawley animals to discriminate possible sex differences in responses to startle. The startle method operates through auditory pathways in brain via a network of sensorimotor gating processes within auditory cortex, cochlear nuclei, inferior and superior colliculi, pontine reticular nuclei, in addition to mesocorticolimbic brain reward and nigrostriatal motor circuitries. This paper is the first to report sex differences to acoustic stimuli in Sprague-Dawley animals (Rattus norvegicus) although such gender responses to acoustic startle have been reported in humans (Swerdlow et al. 1997 [1]). The startle method monitors pre-pulse inhibition (PPI) as a measure of the loss of sensorimotor gating in the brain's neuronal auditory network; auditory deficiencies can lead to sensory overload and subsequently cognitive dysfunction. Cocaine addicts and schizophrenic patients as well as cocaine treated animals are reported to exhibit symptoms of defective PPI (Geyer et al., 2001 [2]). Key findings are: (a) Cocaine significantly reduced PPI in both sexes. (b) Females were significantly more sensitive than males; reduced PPI was greater in females than in males. (c) Physiological saline had no effect on startle in either sex. Thus, the data elucidate gender-specificity to the startle response in animals. Finally, preliminary studies show the effect of cocaine on acoustic startle in tandem with effects on estrous cycle. The data further suggest that hormones may play a role in these sex differences to acoustic startle reported herein. Full article
(This article belongs to the Special Issue Addiction and Neuroadaptation)
Figures

Open AccessArticle Ethanol Modulates Spontaneous Calcium Waves in Axonal Growth Cones in Vitro
Brain Sci. 2013, 3(2), 615-626; doi:10.3390/brainsci3020615
Received: 14 March 2013 / Revised: 12 April 2013 / Accepted: 16 April 2013 / Published: 23 April 2013
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Abstract
In developing neurons the frequency of long duration, spontaneous, transient calcium (Ca2+) elevations localized to the growth cone, is inversely related to the rate of axon elongation and increases several fold when axons pause. Here we report that these spontaneous Ca
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In developing neurons the frequency of long duration, spontaneous, transient calcium (Ca2+) elevations localized to the growth cone, is inversely related to the rate of axon elongation and increases several fold when axons pause. Here we report that these spontaneous Ca2+ transients with slow kinetics, called Ca2+ waves, are modulated by conditions of ethanol exposure that alter axonal growth dynamics. Using time-series fluorescence calcium imaging we found that acute treatment of fetal rat hippocampal neurons with 43 or 87 mM ethanol at an early stage of development in culture decreased the percent of axon growth cones showing at least one Ca2+ wave during 10 min of recording, from 18% in controls to 5% in cultures exposed to ethanol. Chronic exposure to 43 mM ethanol also reduced the incidence of Ca2+ waves to 8%, but exposure to 87 mM ethanol increased their incidence to 31%. Neither chronic nor acute ethanol affected the peak amplitude, time to peak or total duration of Ca2+ waves. In some experiments, we determined the temporal correlation between Ca2+ waves and growth and non-growth phases of axonal growth dynamics. As expected, waves were most prevalent in stationary or retracting growth cones in all treatment groups, except in cultures exposed chronically to 87 mM ethanol. Thus, the relationship between growth cone Ca2+ waves and axon growth dynamics is disrupted by ethanol. Full article
(This article belongs to the Special Issue Ethanol Neurotoxicity)
Open AccessArticle Impact of Repetitive Transcranial Magnetic Stimulation (rTMS) on Brain Functional Marker of Auditory Hallucinations in Schizophrenia Patients
Brain Sci. 2013, 3(2), 728-743; doi:10.3390/brainsci3020728
Received: 8 February 2013 / Revised: 15 March 2013 / Accepted: 9 April 2013 / Published: 29 April 2013
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Abstract
Several cross-sectional functional Magnetic Resonance Imaging (fMRI) studies reported a negative correlation between auditory verbal hallucination (AVH) severity and amplitude of the activations during language tasks. The present study assessed the time course of this correlation and its possible structural underpinnings by combining
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Several cross-sectional functional Magnetic Resonance Imaging (fMRI) studies reported a negative correlation between auditory verbal hallucination (AVH) severity and amplitude of the activations during language tasks. The present study assessed the time course of this correlation and its possible structural underpinnings by combining structural, functional MRI and repetitive Transcranial Magnetic Stimulation (rTMS). Methods: Nine schizophrenia patients with AVH (evaluated with the Auditory Hallucination Rating scale; AHRS) and nine healthy participants underwent two sessions of an fMRI speech listening paradigm. Meanwhile, patients received high frequency (20 Hz) rTMS. Results: Before rTMS, activations were negatively correlated with AHRS in a left posterior superior temporal sulcus (pSTS) cluster, considered henceforward as a functional region of interest (fROI). After rTMS, activations in this fROI no longer correlated with AHRS. This decoupling was explained by a significant decrease of AHRS scores after rTMS that contrasted with a relative stability of cerebral activations. A voxel-based-morphometry analysis evidenced a cluster of the left pSTS where grey matter volume negatively correlated with AHRS before rTMS and positively correlated with activations in the fROI at both sessions. Conclusion: rTMS decreases the severity of AVH leading to modify the functional correlate of AVH underlain by grey matter abnormalities. Full article
(This article belongs to the Special Issue Brain and Language)
Open AccessArticle Differential Effects of Chronic and Chronic-Intermittent Ethanol Treatment and Its Withdrawal on the Expression of miRNAs
Brain Sci. 2013, 3(2), 744-756; doi:10.3390/brainsci3020744
Received: 27 February 2013 / Revised: 11 April 2013 / Accepted: 25 April 2013 / Published: 3 May 2013
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Abstract
Chronic and excessive alcohol misuse results in changes in the expression of selected miRNAs and their mRNA targets in specific regions of the human brain. These expression changes likely underlie the cellular adaptations to long term alcohol misuse. In order to delineate the
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Chronic and excessive alcohol misuse results in changes in the expression of selected miRNAs and their mRNA targets in specific regions of the human brain. These expression changes likely underlie the cellular adaptations to long term alcohol misuse. In order to delineate the mechanism by which these expression changes occur, we have measured the expression of six miRNAs including miR-7, miR-153, miR-152, miR-15B, miR-203 and miR-144 in HEK293T, SH SY5Y and 1321 N1 cells following exposure to ethanol. These miRNAs are predicted to target key genes involved in the pathophysiology of alcoholism. Chronic and chronic-intermittent exposure to ethanol, and its removal, resulted in specific changes in miRNA expression in each cell line suggesting that different expression patterns can be elicited with different exposure paradigms and that the mechanism of ethanol’s effects is dependent on cell type. Specifically, chronic exposure to ethanol for five days followed by a five day withdrawal period resulted in up-regulation of several miRNAs in each of these cell lines similar to expression changes identified in post mortem human brain. Thus, this model can be used to elucidate the role of miRNAs in regulating gene expression changes that occur in response to ethanol exposure. Full article
(This article belongs to the Special Issue Ethanol Neurotoxicity)
Open AccessArticle Changes in Oscillatory Brain Networks after Lexical Tone Training
Brain Sci. 2013, 3(2), 757-780; doi:10.3390/brainsci3020757
Received: 15 January 2013 / Revised: 28 March 2013 / Accepted: 18 April 2013 / Published: 3 May 2013
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Abstract
Learning foreign speech contrasts involves creating new representations of sound categories in memory. This formation of new memory representations is likely to involve changes in neural networks as reflected by oscillatory brain activity. To explore this, we conducted time-frequency analyses of electro-encephalography (EEG)
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Learning foreign speech contrasts involves creating new representations of sound categories in memory. This formation of new memory representations is likely to involve changes in neural networks as reflected by oscillatory brain activity. To explore this, we conducted time-frequency analyses of electro-encephalography (EEG) data recorded in a passive auditory oddball paradigm using Thai language tones. We compared native speakers of English (a non-tone language) and native speakers of Mandarin Chinese (a tone language), before and after a two-day laboratory training. Native English speakers showed a larger gamma-band power and stronger alpha-band synchrony across EEG channels than the native Chinese speakers, especially after training. This is compatible with the view that forming new speech categories on the basis of unfamiliar perceptual dimensions involves stronger gamma activity and more coherent activity in alpha-band networks than forming new categories on the basis of familiar dimensions. Full article
(This article belongs to the Special Issue Brain and Language)
Open AccessArticle Neurovascular Coupling of the Posterior Cerebral Artery in Spinal Cord Injury: A Pilot Study
Brain Sci. 2013, 3(2), 781-789; doi:10.3390/brainsci3020781
Received: 19 February 2013 / Revised: 26 April 2013 / Accepted: 29 April 2013 / Published: 8 May 2013
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Abstract
Purpose: To compare neurovascular coupling in the posterior cerebral artery (PCA) between those with spinal cord injury (SCI) and able bodied (AB) individuals. Methods: A total of seven SCI and seven AB were matched for age and sex. Measures included PCA velocity (PCAv),
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Purpose: To compare neurovascular coupling in the posterior cerebral artery (PCA) between those with spinal cord injury (SCI) and able bodied (AB) individuals. Methods: A total of seven SCI and seven AB were matched for age and sex. Measures included PCA velocity (PCAv), beat-by-beat blood pressure and end-tidal carbon dioxide. Posterior cerebral cortex activation was achieved by 10 cycles of (1) 30 s eyes closed (pre-stimulation), (2) 30 s reading (stimulation). Results: Blood pressure was significantly reduced in those with SCI (SBP: 100 ± 13 mmHg; DBP: 58 ± 13 mmHg) vs. AB (SBP: 121 ± 12 mmHg; DBP: 74 ± 9 mmHg) during both pre-stimulation and stimulation, but the relative increase was similar during the stimulation period. Changes in PCAv during stimulation were mitigated in the SCI group (6% ± 6%) vs. AB (29% ± 12%, P < 0.001). Heart rate and end-tidal carbon dioxide responded similarly between groups. Conclusions: Clearly, NVC is impaired in those with SCI. This study may provide a link between poor perfusion of the posterior cerebral region (containing the medullary autonomic centres) and autonomic dysfunction after SCI. Full article
Open AccessArticle Effects of Lifelong Ethanol Consumption on Brain Monoamine Transmitters in Alcohol-Preferring Alko Alcohol (AA) Rats
Brain Sci. 2013, 3(2), 790-799; doi:10.3390/brainsci3020790
Received: 1 March 2013 / Revised: 2 May 2013 / Accepted: 7 May 2013 / Published: 15 May 2013
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Abstract
The purpose of the present study was to examine the combined effects of aging and lifelong ethanol exposure on the levels of monoamine neurotransmitters in different regions of the brain. This work is part of a project addressing interactions of aging and lifelong
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The purpose of the present study was to examine the combined effects of aging and lifelong ethanol exposure on the levels of monoamine neurotransmitters in different regions of the brain. This work is part of a project addressing interactions of aging and lifelong ethanol consumption in alcohol-preferring AA (Alko Alcohol) line of rats, selected for high voluntary consumption of ethanol. Intake of ethanol on the level of 4.5–5 g/kg/day for about 20 months induced only limited changes in the neurotransmitter levels; the concentration of noradrenaline was significantly reduced in the frontal cortex. There was also a trend towards lower levels of dopamine and 5-hydroxytryptamine (5-HT) in the frontal cortex, and towards a lower noradrenaline level in the dorsal cortex. Aging was associated with a decreased concentration of dopamine in the dorsal cortex and with a declining trend in the striatum. The levels of 5-HT in the limbic forebrain were higher in the aged than in the young animals, and in the striatum, there was a trend towards higher levels in older animals. The data suggest that a continuous intake of moderate amounts of ethanol does not enhance the age-related alterations in brain monoamine neurotransmission, while the decline in the brain level of dopamine associated with aging may be a factor contributing to age-related neurological disorders. Full article
(This article belongs to the Special Issue Ethanol Neurotoxicity)
Open AccessArticle The Health Benefits and Challenges of Exercise Training in Persons Living with Schizophrenia: A Pilot Study
Brain Sci. 2013, 3(2), 821-848; doi:10.3390/brainsci3020821
Received: 11 April 2013 / Revised: 3 May 2013 / Accepted: 7 May 2013 / Published: 24 May 2013
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Abstract
Background: In addition to the hallmark cognitive and functional impairments mounting evidence indicates that schizophrenia is also associated with an increased risk for the development of secondary complications, in particular cardio-metabolic disease. This is thought to be the result of various factors including
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Background: In addition to the hallmark cognitive and functional impairments mounting evidence indicates that schizophrenia is also associated with an increased risk for the development of secondary complications, in particular cardio-metabolic disease. This is thought to be the result of various factors including physical inactivity and the metabolic side effects of psychotropic medications. Therefore, non-pharmacological approaches to improving brain health, physical health, and overall well-being have been promoted increasingly. Methods: We report on the health-related physical fitness (body composition, blood pressure, heart rate, and aerobic fitness) and lipid profile of persons living with schizophrenia and effective means to address the challenges of exercise training in this population. Results: There was a markedly increased risk for cardio-metabolic disease in 13 persons living with schizophrenia (Age = 31 ± 7 years) including low aerobic fitness (76% ± 34% of predicted), reduced HDL (60% of cohort), elevated resting heart rate (80% of cohort), hypertension (40% of cohort), overweight and obesity (69% of cohort), and abdominal obesity (54% of cohort). Individualized exercise prescription (3 times/week) was well tolerated, with no incidence of adverse exercise-related events. The exercise adherence rate was 81% ± 21% (Range 48%–100%), and 69% of the participants were able to complete the entire exercise training program. Exercise training resulted in clinically important changes in physical activity, aerobic fitness, exercise tolerance, blood pressure, and body composition. Conclusion: Persons living with schizophrenia appear to be at an increased risk for cardio-metabolic disease. An individualized exercise program has shown early promise for the treatment of schizophrenia and the various cognitive, functional, and physiological impairments that ultimately affect health and well-being. Full article
(This article belongs to the Special Issue Exercise and Brain Function)
Open AccessArticle Multilingualism and fMRI: Longitudinal Study of Second Language Acquisition
Brain Sci. 2013, 3(2), 849-876; doi:10.3390/brainsci3020849
Received: 5 March 2013 / Revised: 3 May 2013 / Accepted: 7 May 2013 / Published: 28 May 2013
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Abstract
BOLD fMRI is often used for the study of human language. However, there are still very few attempts to conduct longitudinal fMRI studies in the study of language acquisition by measuring auditory comprehension and reading. The following paper is the first in a
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BOLD fMRI is often used for the study of human language. However, there are still very few attempts to conduct longitudinal fMRI studies in the study of language acquisition by measuring auditory comprehension and reading. The following paper is the first in a series concerning a unique longitudinal study devoted to the analysis of bi- and multilingual subjects who are: (1) already proficient in at least two languages; or (2) are acquiring Russian as a second/third language. The focus of the current analysis is to present data from the auditory sections of a set of three scans acquired from April, 2011 through April, 2012 on a five-person subject pool who are learning Russian during the study. All subjects were scanned using the same protocol for auditory comprehension on the same General Electric LX 3T Signa scanner in Duke University Hospital. Using a multivariate analysis of covariance (MANCOVA) for statistical analysis, proficiency measurements are shown to correlate significantly with scan results in the Russian conditions over time. The importance of both the left and right hemispheres in language processing is discussed. Special attention is devoted to the importance of contextualizing imaging data with corresponding behavioral and empirical testing data using a multivariate analysis of variance. This is the only study to date that includes: (1) longitudinal fMRI data with subject-based proficiency and behavioral data acquired in the same time frame; and (2) statistical modeling that demonstrates the importance of covariate language proficiency data for understanding imaging results of language acquisition. Full article
(This article belongs to the Special Issue Brain and Language)
Open AccessArticle Congenital Unilateral Deafness Affects Cerebral Organization of Reading
Brain Sci. 2013, 3(2), 908-922; doi:10.3390/brainsci3020908
Received: 8 March 2013 / Revised: 17 May 2013 / Accepted: 22 May 2013 / Published: 5 June 2013
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Abstract
It is known that early sensory deprivation modifies brain functional structure and connectivity. The aim of the present study was to investigate the neuro-functional organization of reading in a patient with profound congenital unilateral deafness. Using event-related potentials (ERPs), we compared
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It is known that early sensory deprivation modifies brain functional structure and connectivity. The aim of the present study was to investigate the neuro-functional organization of reading in a patient with profound congenital unilateral deafness. Using event-related potentials (ERPs), we compared cortical networks supporting the processing of written words in patient RA (completely deaf in the right ear since birth) and in a group of control volunteers. We found that congenital unilateral hearing deprivation modifies neural mechanisms of word reading. Indeed, while written word processing was left-lateralized in controls, we found a strong right lateralization of the fusiform and inferior occipital gyri activation in RA. This finding goes in the same direction of recent proposals that the ventral occipito-temporal activity in word reading seem to lateralize to the same hemisphere as the one involved in spoken language processing. Full article
(This article belongs to the Special Issue Brain and Language)
Figures

Open AccessArticle Ethanol Neurotoxicity in the Developing Cerebellum: Underlying Mechanisms and Implications
Brain Sci. 2013, 3(2), 941-963; doi:10.3390/brainsci3020941
Received: 11 April 2013 / Revised: 8 May 2013 / Accepted: 4 June 2013 / Published: 14 June 2013
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Abstract
Ethanol is the main constituent of alcoholic beverages that exerts toxicity to neuronal development. Ethanol affects synaptogenesis and prevents proper brain development. In humans, synaptogenesis takes place during the third trimester of pregnancy, and in rodents this period corresponds to the initial few
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Ethanol is the main constituent of alcoholic beverages that exerts toxicity to neuronal development. Ethanol affects synaptogenesis and prevents proper brain development. In humans, synaptogenesis takes place during the third trimester of pregnancy, and in rodents this period corresponds to the initial few weeks of postnatal development. In this period neuronal maturation and differentiation begin and neuronal cells start migrating to their ultimate destinations. Although the neuronal development of all areas of the brain is affected, the cerebellum and cerebellar neurons are more susceptible to the damaging effects of ethanol. Ethanol’s harmful effects include neuronal cell death, impaired differentiation, reduction of neuronal numbers, and weakening of neuronal plasticity. Neuronal development requires many hormones and growth factors such as retinoic acid, nerve growth factors, and cytokines. These factors regulate development and differentiation of neurons by acting through various receptors and their signaling pathways. Ethanol exposure during development impairs neuronal signaling mechanisms mediated by the N-methyl-d-aspartate (NMDA) receptors, the retinoic acid receptors, and by growth factors such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-I), and basic fibroblast growth factor (bFGF). In combination, these ethanol effects disrupt cellular homeostasis, reduce the survival and migration of neurons, and lead to various developmental defects in the brain. Here we review the signaling mechanisms that are required for proper neuronal development, and how these processes are impaired by ethanol resulting in harmful consequences to brain development. Full article
(This article belongs to the Special Issue Ethanol Neurotoxicity)

Review

Jump to: Research, Other

Open AccessReview Endovascular Thrombectomy Following Acute Ischemic Stroke: A Single-Center Case Series and Critical Review of the Literature
Brain Sci. 2013, 3(2), 521-539; doi:10.3390/brainsci3020521
Received: 14 February 2013 / Revised: 26 March 2013 / Accepted: 28 March 2013 / Published: 12 April 2013
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Abstract
Acute ischemic stroke (AIS) due to thrombo-embolic occlusion in the cerebral vasculature is a major cause of morbidity and mortality in the United States and throughout the world. Although the prognosis is poor for many patients with AIS, a variety of strategies and
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Acute ischemic stroke (AIS) due to thrombo-embolic occlusion in the cerebral vasculature is a major cause of morbidity and mortality in the United States and throughout the world. Although the prognosis is poor for many patients with AIS, a variety of strategies and devices are now available for achieving recanalization in patients with this disease. Here, we review the treatment options for cerebrovascular thromboembolic occlusion with a focus on the evolution of strategies and devices that are utilized for achieving endovascular clot extraction. In order to demonstrate the progression of this treatment strategy over the past decade, we will also present a single-center case series of AIS patients treated with endovascular thrombectomy. Full article
(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)
Open AccessReview Stroke Neuroprotection: Targeting Mitochondria
Brain Sci. 2013, 3(2), 540-560; doi:10.3390/brainsci3020540
Received: 8 March 2013 / Revised: 8 April 2013 / Accepted: 9 April 2013 / Published: 19 April 2013
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Abstract
Stroke is the fourth leading cause of death and the leading cause of long-term disability in the United States. Blood flow deficit results in an expanding infarct core with a time-sensitive peri-infarct penumbra that is considered salvageable and is the primary target for
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Stroke is the fourth leading cause of death and the leading cause of long-term disability in the United States. Blood flow deficit results in an expanding infarct core with a time-sensitive peri-infarct penumbra that is considered salvageable and is the primary target for treatment strategies. The only current FDA-approved drug for treating ischemic stroke is recombinant tissue plasminogen activator (rt-PA). However, this treatment is limited to within 4.5 h of stroke onset in a small subset of patients. The goal of this review is to focus on mitochondrial-dependent therapeutic agents that could provide neuroprotection following stroke. Dysfunctional mitochondria are linked to neurodegeneration in many disease processes including stroke. The mechanisms reviewed include: (1) increasing ATP production by purinergic receptor stimulation, (2) decreasing the production of ROS by superoxide dismutase, or (3) increasing antioxidant defenses by methylene blue, and their benefits in providing neuroprotection following a stroke. Full article
(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)
Open AccessReview NADPH Oxidase as a Therapeutic Target for Neuroprotection against Ischaemic Stroke: Future Perspectives
Brain Sci. 2013, 3(2), 561-598; doi:10.3390/brainsci3020561
Received: 31 January 2013 / Revised: 14 March 2013 / Accepted: 20 March 2013 / Published: 22 April 2013
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Abstract
Oxidative stress caused by an excess of reactive oxygen species (ROS) is known to contribute to stroke injury, particularly during reperfusion, and antioxidants targeting this process have resulted in improved outcomes experimentally. Unfortunately these improvements have not been successfully translated to the clinical
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Oxidative stress caused by an excess of reactive oxygen species (ROS) is known to contribute to stroke injury, particularly during reperfusion, and antioxidants targeting this process have resulted in improved outcomes experimentally. Unfortunately these improvements have not been successfully translated to the clinical setting. Targeting the source of oxidative stress may provide a superior therapeutic approach. The NADPH oxidases are a family of enzymes dedicated solely to ROS production and pre-clinical animal studies targeting NADPH oxidases have shown promising results. However there are multiple factors that need to be considered for future drug development: There are several homologues of the catalytic subunit of NADPH oxidase. All have differing physiological roles and may contribute differentially to oxidative damage after stroke. Additionally, the role of ROS in brain repair is largely unexplored, which should be taken into consideration when developing drugs that inhibit specific NADPH oxidases after injury. This article focuses on the current knowledge regarding NADPH oxidase after stroke including in vivo genetic and inhibitor studies. The caution required when interpreting reports of positive outcomes after NADPH oxidase inhibition is also discussed, as effects on long term recovery are yet to be investigated and are likely to affect successful clinical translation. Full article
(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)
Open AccessReview Neural Repair and Neuroprotection with Stem Cells in Ischemic Stroke
Brain Sci. 2013, 3(2), 599-614; doi:10.3390/brainsci3020599
Received: 31 January 2013 / Revised: 12 April 2013 / Accepted: 12 April 2013 / Published: 23 April 2013
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Abstract
Stem cells have been touted as a potential source of cells for repair in regenerative medicine. When transplanted into the central nervous system, stem cells have been shown to differentiate into neurons and glia. Recent studies, however, have also revealed neuroprotective properties of
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Stem cells have been touted as a potential source of cells for repair in regenerative medicine. When transplanted into the central nervous system, stem cells have been shown to differentiate into neurons and glia. Recent studies, however, have also revealed neuroprotective properties of stem cells. These studies suggest that various types of stem cells are able to protect against the loss of neurons in conditions of ischemic brain injury. In this article, we discuss the use of stem cells for ischemic stroke and the parameters under which neuroprotection can occur in the translation of stem cell therapy to the clinical setting. Full article
(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)
Open AccessReview Human Temporal Cortical Single Neuron Activity during Language: A Review
Brain Sci. 2013, 3(2), 627-641; doi:10.3390/brainsci3020627
Received: 7 March 2013 / Accepted: 8 April 2013 / Published: 26 April 2013
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Abstract
Findings from recordings of human temporal cortical single neuron activity during several measures of language, including object naming and word reading are reviewed and related to changes in activity in the same neurons during recent verbal memory and verbal associative learning measures, in
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Findings from recordings of human temporal cortical single neuron activity during several measures of language, including object naming and word reading are reviewed and related to changes in activity in the same neurons during recent verbal memory and verbal associative learning measures, in studies conducted during awake neurosurgery for the treatment of epilepsy. The proportion of neurons changing activity with language tasks was similar in either hemisphere. Dominant hemisphere activity was characterized by relative inhibition, some of which occurred during overt speech, possibly to block perception of one’s own voice. However, the majority seems to represent a dynamic network becoming active with verbal memory encoding and especially verbal learning, but inhibited during performance of overlearned language tasks. Individual neurons are involved in different networks for different aspects of language, including naming or reading and naming in different languages. The majority of the changes in activity were tonic sustained shifts in firing. Patterned phasic activity for specific language items was very infrequently recorded. Human single neuron recordings provide a unique perspective on the biologic substrate for language, for these findings are in contrast to many of the findings from other techniques for investigating this. Full article
(This article belongs to the Special Issue Brain and Language)
Open AccessReview Mechanisms Underlying Auditory Hallucinations—Understanding Perception without Stimulus
Brain Sci. 2013, 3(2), 642-669; doi:10.3390/brainsci3020642
Received: 21 March 2013 / Revised: 7 April 2013 / Accepted: 18 April 2013 / Published: 26 April 2013
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Abstract
Auditory verbal hallucinations (AVH) are a common phenomenon, occurring in the “healthy” population as well as in several mental illnesses, most notably schizophrenia. Current thinking supports a spectrum conceptualisation of AVH: several neurocognitive hypotheses of AVH have been proposed, including the “feed-forward” model
[...] Read more.
Auditory verbal hallucinations (AVH) are a common phenomenon, occurring in the “healthy” population as well as in several mental illnesses, most notably schizophrenia. Current thinking supports a spectrum conceptualisation of AVH: several neurocognitive hypotheses of AVH have been proposed, including the “feed-forward” model of failure to provide appropriate information to somatosensory cortices so that stimuli appear unbidden, and an “aberrant memory model” implicating deficient memory processes. Neuroimaging and connectivity studies are in broad agreement with these with a general dysconnectivity between frontotemporal regions involved in language, memory and salience properties. Disappointingly many AVH remain resistant to standard treatments and persist for many years. There is a need to develop novel therapies to augment existing pharmacological and psychological therapies: transcranial magnetic stimulation has emerged as a potential treatment, though more recent clinical data has been less encouraging. Our understanding of AVH remains incomplete though much progress has been made in recent years. We herein provide a broad overview and review of this. Full article
(This article belongs to the Special Issue Brain and Language)
Open AccessReview Involvement of Sphingolipids in Ethanol Neurotoxicity in the Developing Brain
Brain Sci. 2013, 3(2), 670-703; doi:10.3390/brainsci3020670
Received: 21 February 2013 / Revised: 30 March 2013 / Accepted: 12 April 2013 / Published: 26 April 2013
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Abstract
Ethanol-induced neuronal death during a sensitive period of brain development is considered one of the significant causes of fetal alcohol spectrum disorders (FASD). In rodent models, ethanol triggers robust apoptotic neurodegeneration during a period of active synaptogenesis that occurs around the first two
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Ethanol-induced neuronal death during a sensitive period of brain development is considered one of the significant causes of fetal alcohol spectrum disorders (FASD). In rodent models, ethanol triggers robust apoptotic neurodegeneration during a period of active synaptogenesis that occurs around the first two postnatal weeks, equivalent to the third trimester in human fetuses. The ethanol-induced apoptosis is mitochondria-dependent, involving Bax and caspase-3 activation. Such apoptotic pathways are often mediated by sphingolipids, a class of bioactive lipids ubiquitously present in eukaryotic cellular membranes. While the central role of lipids in ethanol liver toxicity is well recognized, the involvement of sphingolipids in ethanol neurotoxicity is less explored despite mounting evidence of their importance in neuronal apoptosis. Nevertheless, recent studies indicate that ethanol-induced neuronal apoptosis in animal models of FASD is mediated or regulated by cellular sphingolipids, including via the pro-apoptotic action of ceramide and through the neuroprotective action of GM1 ganglioside. Such sphingolipid involvement in ethanol neurotoxicity in the developing brain may provide unique targets for therapeutic applications against FASD. Here we summarize findings describing the involvement of sphingolipids in ethanol-induced apoptosis and discuss the possibility that the combined action of various sphingolipids in mitochondria may control neuronal cell fate. Full article
(This article belongs to the Special Issue Ethanol Neurotoxicity)
Open AccessReview Long-Lasting Neural Circuit Dysfunction Following Developmental Ethanol Exposure
Brain Sci. 2013, 3(2), 704-727; doi:10.3390/brainsci3020704
Received: 27 February 2013 / Revised: 10 April 2013 / Accepted: 23 April 2013 / Published: 29 April 2013
Cited by 10 | PDF Full-text (554 KB) | HTML Full-text | XML Full-text
Abstract
Fetal Alcohol Spectrum Disorder (FASD) is a general diagnosis for those exhibiting long-lasting neurobehavioral and cognitive deficiencies as a result of fetal alcohol exposure. It is among the most common causes of mental deficits today. Those impacted are left to rely on advances
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Fetal Alcohol Spectrum Disorder (FASD) is a general diagnosis for those exhibiting long-lasting neurobehavioral and cognitive deficiencies as a result of fetal alcohol exposure. It is among the most common causes of mental deficits today. Those impacted are left to rely on advances in our understanding of the nature of early alcohol-induced disorders toward human therapies. Research findings over the last decade have developed a model where ethanol-induced neurodegeneration impacts early neural circuit development, thereby perpetuating subsequent integration and plasticity in vulnerable brain regions. Here we review our current knowledge of FASD neuropathology based on discoveries of long-lasting neurophysiological effects of acute developmental ethanol exposure in animal models. We discuss the important balance between synaptic excitation and inhibition in normal neural network function, and relate the significance of that balance to human FASD as well as related disease states. Finally, we postulate that excitation/inhibition imbalance caused by early ethanol-induced neurodegeneration results in perturbed local and regional network signaling and therefore neurobehavioral pathology. Full article
(This article belongs to the Special Issue Ethanol Neurotoxicity)
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Open AccessReview From Neural Plate to Cortical Arousal—A Neuronal Network Theory of Sleep Derived from in Vitro “Model” Systems for Primordial Patterns of Spontaneous Bioelectric Activity in the Vertebrate Central Nervous System
Brain Sci. 2013, 3(2), 800-820; doi:10.3390/brainsci3020800
Received: 11 March 2013 / Revised: 15 April 2013 / Accepted: 6 May 2013 / Published: 22 May 2013
Cited by 4 | PDF Full-text (2707 KB) | HTML Full-text | XML Full-text
Abstract
In the early 1960s intrinsically generated widespread neuronal discharges were discovered to be the basis for the earliest motor behavior throughout the animal kingdom. The pattern generating system is in fact programmed into the developing nervous system, in a regionally specific manner, already
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In the early 1960s intrinsically generated widespread neuronal discharges were discovered to be the basis for the earliest motor behavior throughout the animal kingdom. The pattern generating system is in fact programmed into the developing nervous system, in a regionally specific manner, already at the early neural plate stage. Such rhythmically modulated phasic bursts were next discovered to be a general feature of developing neural networks and, largely on the basis of experimental interventions in cultured neural tissues, to contribute significantly to their morpho-physiological maturation. In particular, the level of spontaneous synchronized bursting is homeostatically regulated, and has the effect of constraining the development of excessive network excitability. After birth or hatching, this “slow-wave” activity pattern becomes sporadically suppressed in favor of sensory oriented “waking” behaviors better adapted to dealing with environmental contingencies. It nevertheless reappears periodically as “sleep” at several species-specific points in the diurnal/nocturnal cycle. Although this “default” behavior pattern evolves with development, its essential features are preserved throughout the life cycle, and are based upon a few simple mechanisms which can be both experimentally demonstrated and simulated by computer modeling. In contrast, a late onto- and phylogenetic aspect of sleep, viz., the intermittent “paradoxical” activation of the forebrain so as to mimic waking activity, is much less well understood as regards its contribution to brain development. Some recent findings dealing with this question by means of cholinergically induced “aroused” firing patterns in developing neocortical cell cultures, followed by quantitative electrophysiological assays of immediate and longterm sequelae, will be discussed in connection with their putative implications for sleep ontogeny. Full article
(This article belongs to the Special Issue Sleep and Brain Development)
Open AccessReview Neuroprotective Mechanisms of Taurine against Ischemic Stroke
Brain Sci. 2013, 3(2), 877-907; doi:10.3390/brainsci3020877
Received: 15 February 2013 / Revised: 14 May 2013 / Accepted: 17 May 2013 / Published: 3 June 2013
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Abstract
Ischemic stroke exhibits a multiplicity of pathophysiological mechanisms. To address the diverse pathophysiological mechanisms observed in ischemic stroke investigators seek to find therapeutic strategies that are multifaceted in their action by either investigating multipotential compounds or by using a combination of compounds. Taurine,
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Ischemic stroke exhibits a multiplicity of pathophysiological mechanisms. To address the diverse pathophysiological mechanisms observed in ischemic stroke investigators seek to find therapeutic strategies that are multifaceted in their action by either investigating multipotential compounds or by using a combination of compounds. Taurine, an endogenous amino acid, exhibits a plethora of physiological functions. It exhibits antioxidative properties, stabilizes membrane, functions as an osmoregulator, modulates ionic movements, reduces the level of pro-inflammators, regulates intracellular calcium concentration; all of which contributes to its neuroprotective effect. Data are accumulating that show the neuroprotective mechanisms of taurine against stroke pathophysiology. In this review, we describe the neuroprotective mechanisms employed by taurine against ischemic stroke and its use in clinical trial for ischemic stroke. Full article
(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)
Open AccessReview Musical Expertise and Second Language Learning
Brain Sci. 2013, 3(2), 923-940; doi:10.3390/brainsci3020923
Received: 3 April 2013 / Revised: 23 May 2013 / Accepted: 24 May 2013 / Published: 6 June 2013
Cited by 6 | PDF Full-text (244 KB) | HTML Full-text | XML Full-text
Abstract
Increasing evidence suggests that musical expertise influences brain organization and brain functions. Moreover, results at the behavioral and neurophysiological levels reveal that musical expertise positively influences several aspects of speech processing, from auditory perception to speech production. In this review, we focus on
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Increasing evidence suggests that musical expertise influences brain organization and brain functions. Moreover, results at the behavioral and neurophysiological levels reveal that musical expertise positively influences several aspects of speech processing, from auditory perception to speech production. In this review, we focus on the main results of the literature that led to the idea that musical expertise may benefit second language acquisition. We discuss several interpretations that may account for the influence of musical expertise on speech processing in native and foreign languages, and we propose new directions for future research. Full article
(This article belongs to the Special Issue Brain and Language)
Open AccessReview Fetal Alcohol Spectrum Disorder (FASD) Associated Neural Defects: Complex Mechanisms and Potential Therapeutic Targets
Brain Sci. 2013, 3(2), 964-991; doi:10.3390/brainsci3020964
Received: 1 April 2013 / Revised: 3 June 2013 / Accepted: 4 June 2013 / Published: 19 June 2013
Cited by 11 | PDF Full-text (2180 KB) | HTML Full-text | XML Full-text
Abstract
Fetal alcohol spectrum disorder (FASD), caused by prenatal alcohol exposure, can result in craniofacial dysmorphism, cognitive impairment, sensory and motor disabilities among other defects. FASD incidences are as high as 2% to 5 % children born in the US, and prevalence is higher
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Fetal alcohol spectrum disorder (FASD), caused by prenatal alcohol exposure, can result in craniofacial dysmorphism, cognitive impairment, sensory and motor disabilities among other defects. FASD incidences are as high as 2% to 5 % children born in the US, and prevalence is higher in low socioeconomic populations. Despite various mechanisms being proposed to explain the etiology of FASD, the molecular targets of ethanol toxicity during development are unknown. Proposed mechanisms include cell death, cell signaling defects and gene expression changes. More recently, the involvement of several other molecular pathways was explored, including non-coding RNA, epigenetic changes and specific vitamin deficiencies. These various pathways may interact, producing a wide spectrum of consequences. Detailed understanding of these various pathways and their interactions will facilitate the therapeutic target identification, leading to new clinical intervention, which may reduce the incidence and severity of these highly prevalent preventable birth defects. This review discusses manifestations of alcohol exposure on the developing central nervous system, including the neural crest cells and sensory neural placodes, focusing on molecular neurodevelopmental pathways as possible therapeutic targets for prevention or protection. Full article
(This article belongs to the Special Issue Ethanol Neurotoxicity)
Open AccessReview Neuromolecular Imaging Shows Temporal Synchrony Patterns between Serotonin and Movement within Neuronal Motor Circuits in the Brain
Brain Sci. 2013, 3(2), 992-1012; doi:10.3390/brainsci3020992
Received: 12 April 2013 / Revised: 3 June 2013 / Accepted: 4 June 2013 / Published: 21 June 2013
Cited by 1 | PDF Full-text (3515 KB) | HTML Full-text | XML Full-text
Abstract
The present discourse links the electrical and chemical properties of the brain with neurotransmitters and movement behaviors to further elucidate strategies to diagnose and treat brain disease. Neuromolecular imaging (NMI), based on electrochemical principles, is used to detect serotonin in nerve terminals (dorsal
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The present discourse links the electrical and chemical properties of the brain with neurotransmitters and movement behaviors to further elucidate strategies to diagnose and treat brain disease. Neuromolecular imaging (NMI), based on electrochemical principles, is used to detect serotonin in nerve terminals (dorsal and ventral striata) and somatodendrites (ventral tegmentum) of reward/motor mesocorticolimbic and nigrostriatal brain circuits. Neuronal release of serotonin is detected at the same time and in the same animal, freely moving and unrestrained, while open-field behaviors are monitored via infrared photobeams. The purpose is to emphasize the unique ability of NMI and the BRODERICK PROBE® biosensors to empirically image a pattern of temporal synchrony, previously reported, for example, in Aplysia using central pattern generators (CPGs), serotonin and cerebral peptide-2. Temporal synchrony is reviewed within the context of the literature on central pattern generators, neurotransmitters and movement disorders. Specifically, temporal synchrony data are derived from studies on psychostimulant behavior with and without cocaine while at the same time and continuously, serotonin release in motor neurons within basal ganglia, is detected. The results show that temporal synchrony between the neurotransmitter, serotonin and natural movement occurs when the brain is NOT injured via, e.g., trauma, addictive drugs or psychiatric illness. In striking contrast, in the case of serotonin and cocaine-induced psychostimulant behavior, a different form of synchrony and also asynchrony can occur. Thus, the known dysfunctional movement behavior produced by cocaine may well be related to the loss of temporal synchrony, the loss of the ability to match serotonin in brain with motor activity. The empirical study of temporal synchrony patterns in humans and animals may be more relevant to the dynamics of motor circuits and movement behaviors than are studies of static parameters currently relied upon within the realms of science and medicine. There are myriad applications for the use of NMI to discover clinically relevant diagnoses and treatments for brain disease involving the motor system. Full article
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Open AccessConcept Paper A Program for Solving the Brain Ischemia Problem
Brain Sci. 2013, 3(2), 460-503; doi:10.3390/brainsci3020460
Received: 15 January 2013 / Revised: 23 March 2013 / Accepted: 26 March 2013 / Published: 8 April 2013
Cited by 2 | PDF Full-text (3273 KB) | HTML Full-text | XML Full-text
Abstract
Our recently described nonlinear dynamical model of cell injury is here applied to the problems of brain ischemia and neuroprotection. We discuss measurement of global brain ischemia injury dynamics by time course analysis. Solutions to proposed experiments are simulated using hypothetical values for
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Our recently described nonlinear dynamical model of cell injury is here applied to the problems of brain ischemia and neuroprotection. We discuss measurement of global brain ischemia injury dynamics by time course analysis. Solutions to proposed experiments are simulated using hypothetical values for the model parameters. The solutions solve the global brain ischemia problem in terms of “master bifurcation diagrams” that show all possible outcomes for arbitrary durations of all lethal cerebral blood flow (CBF) decrements. The global ischemia master bifurcation diagrams: (1) can map to a single focal ischemia insult, and (2) reveal all CBF decrements susceptible to neuroprotection. We simulate measuring a neuroprotectant by time course analysis, which revealed emergent nonlinear effects that set dynamical limits on neuroprotection. Using over-simplified stroke geometry, we calculate a theoretical maximum protection of approximately 50% recovery. We also calculate what is likely to be obtained in practice and obtain 38% recovery; a number close to that often reported in the literature. The hypothetical examples studied here illustrate the use of the nonlinear cell injury model as a fresh avenue of approach that has the potential, not only to solve the brain ischemia problem, but also to advance the technology of neuroprotection. Full article
(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

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