BioMed Research International: Neuroscience The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Hippocampal-Prefrontal Circuit and Disrupted Functional Connectivity in Psychiatric and Neurodegenerative Disorders Tue, 31 Mar 2015 13:42:49 +0000 In rodents, the hippocampus has been studied extensively as part of a brain system responsible for learning and memory, and the prefrontal cortex (PFC) participates in numerous cognitive functions including working memory, flexibility, decision making, and rewarding learning. The neuronal projections from the hippocampus, either directly or indirectly, to the PFC, referred to as the hippocampal-prefrontal cortex (Hip-PFC) circuit, play a critical role in cognitive and emotional regulation and memory consolidation. Although in certain psychiatric and neurodegenerative diseases, structural connectivity viewed by imaging techniques has been consistently found to be associated with clinical phenotype and disease severity, the focus has moved towards the investigation of connectivity correlates of molecular pathology and coupling of oscillation. Moreover, functional and structural connectivity measures have been emerging as potential intermediate biomarkers for neuronal disorders. In this review, we summarize progress on the anatomic, molecular, and electrophysiological characters of the Hip-PFC circuit in cognition and emotion processes with an emphasis on oscillation and functional connectivity, revealing a disrupted Hip-PFC connectivity and electrical activity in psychiatric and neurodegenerative disorders as a promising candidate of neural marker for neuronal disorders. Ming Li, Cheng Long, and Li Yang Copyright © 2015 Ming Li et al. All rights reserved. Effects of PMA (PHORBOL-12-MYRISTATE-13-ACETATE) on the Developing Rodent Brain Mon, 30 Mar 2015 09:05:34 +0000 Perinatal infections have a negative impact on brain development. However, the underlying mechanisms leading to neurological impairment are not completely understood and reliable models of inflammation are urgently needed. Using phorbol-myristate-acetate as an activator of inflammation, we investigated the effect on the developing rodent brain. Neonatal rats and mice deficient in IL-18 or IRAK-4 were exposed to PMA. Brains were assessed for regulation of pro- and anti-inflammatory cytokines and cell death 24 hrs, 7 and 14 days after treatment. PMA induced an inflammatory response and caused widespread neurodegeneration in the brains of 3- and 7-day-old rats. In contrast, 14-day-old rats were resistant to the neurotoxic effect of PMA. Histological evaluation at the age of 14 and 21 days revealed a destruction of the cortical microstructure with decreased numerical density of neuronal cells. Mice deficient in IL-18 or IRAK-4 were protected against PMA induced brain injury. PMA treatment during a vulnerable period can alter brain development. IL-18 and IRAK-4 appear to be important for the development of PMA induced injury. Mark Dzietko, Maria Hahnemann, Oliver Polley, Marco Sifringer, Ursula Felderhoff-Mueser, and Christoph Bührer Copyright © 2015 Mark Dzietko et al. All rights reserved. Regulating Rac in the Nervous System: Molecular Function and Disease Implication of Rac GEFs and GAPs Tue, 24 Mar 2015 09:00:11 +0000 Rho family GTPases, including RhoA, Rac1, and Cdc42 as the most studied members, are master regulators of actin cytoskeletal organization. Rho GTPases control various aspects of the nervous system and are associated with a number of neuropsychiatric and neurodegenerative diseases. The activity of Rho GTPases is controlled by two families of regulators, guanine nucleotide exchange factors (GEFs) as the activators and GTPase-activating proteins (GAPs) as the inhibitors. Through coordinated regulation by GEFs and GAPs, Rho GTPases act as converging signaling molecules that convey different upstream signals in the nervous system. So far, more than 70 members of either GEFs or GAPs of Rho GTPases have been identified in mammals, but only a small subset of them have well-known functions. Thus, characterization of important GEFs and GAPs in the nervous system is crucial for the understanding of spatiotemporal dynamics of Rho GTPase activity in different neuronal functions. In this review, we summarize the current understanding of GEFs and GAPs for Rac1, with emphasis on the molecular function and disease implication of these regulators in the nervous system. Yanyang Bai, Xiaoliang Xiang, Chunmei Liang, and Lei Shi Copyright © 2015 Yanyang Bai et al. All rights reserved. Chronic Pain: New Insights in Molecular and Cellular Mechanisms Mon, 23 Mar 2015 13:30:15 +0000 Livio Luongo, Marzia Malcangio, Daniela Salvemini, and Katarzyna Starowicz Copyright © 2015 Livio Luongo et al. All rights reserved. Delay of Morphine Tolerance by Palmitoylethanolamide Sun, 22 Mar 2015 08:57:36 +0000 In spite of the potency and efficacy of morphine, its clinical application for chronic persistent pain is limited by the development of tolerance to the antinociceptive effect. The cellular and molecular mechanisms underlying morphine tolerance are complex and still unclear. Recently, the activation of glial cells and the release of glia-derived proinflammatory mediators have been suggested to play a role in the phenomenon. N-Palmitoylethanolamine (PEA) is an endogenous compound with antinociceptive effects able to reduce the glial activation. On this basis, 30 mg kg−1 PEA was subcutaneously daily administered in morphine treated rats (10 mg kg−1 intraperitoneally, daily). PEA treatment significantly attenuated the development of tolerance doubling the number of days of morphine antinociceptive efficacy in comparison to the vehicle + morphine group. PEA prevented both microglia and astrocyte cell number increase induced by morphine in the dorsal horn; on the contrary, the morphine-dependent increase of spinal TNF- levels was not modified by PEA. Nevertheless, the immunohistochemical analysis revealed significantly higher TNF- immunoreactivity in astrocytes of PEA-protected rats suggesting a PEA-mediated decrease of cytokine release from astrocyte. PEA intervenes in the nervous alterations that lead to the lack of morphine antinociceptive effects; a possible application of this endogenous compound in opioid-based therapies is suggested. Lorenzo Di Cesare Mannelli, Francesca Corti, Laura Micheli, Matteo Zanardelli, and Carla Ghelardini Copyright © 2015 Lorenzo Di Cesare Mannelli et al. All rights reserved. Parkinsonism in Spinocerebellar Ataxia Thu, 19 Mar 2015 07:24:33 +0000 Spinocerebellar ataxia (SCA) presents heterogeneous clinical phenotypes, and parkinsonism is reported in diverse SCA subtypes. Both levodopa responsive Parkinson disease (PD) like phenotype and atypical parkinsonism have been described especially in SCA2, SCA3, and SCA17 with geographic differences in prevalence. SCA2 is the most frequently reported subtype of SCA related to parkinsonism worldwide. Parkinsonism in SCA2 has unique genetic characteristics, such as low number of expansions and interrupted structures, which may explain the sporadic cases with low penetrance. Parkinsonism in SCA17 is more remarkable in Asian populations especially in Korea. In addition, an unclear cutoff of the pathologic range is the key issue in SCA17 related parkinsonism. SCA3 is more common in western cohorts. SCA6 and SCA8 have also been reported with a PD-like phenotype. Herein, we reviewed the epidemiologic, clinical, genetic, and pathologic features of parkinsonism in SCAs. Hyeyoung Park, Han-Joon Kim, and Beom S. Jeon Copyright © 2015 Hyeyoung Park et al. All rights reserved. Could α-Synuclein Amyloid-Like Aggregates Trigger a Prionic Neuronal Invasion? Thu, 19 Mar 2015 06:47:12 +0000 Parkinson’s disease (PD), a progressive neurodegenerative disease primarily affecting voluntary and controlled movement, is characterized by abnormal accumulations of α-synuclein (α-syn) in intraneuronal Lewy bodies. In the last years, the increased number of evidences from both the in vitro and in vivo studies has shown the ability of α-syn to misfold in amyloid conformations and to spread via neuron-to-neuron transmission, suggesting a prion-like behaviour. However, in contrast to prion protein (PrP), α-syn transmission is far from neuronal invasion. The high neuronal toxicity of both mature fibres and oligomeric species, as well as the intracellular localization of the protein and the difficulty to be secreted, could be key factors impeding the prion ability of α-syn aggregates. Maria Antònia Busquets, Alba Espargaró, Joan Estelrich, and Raimon Sabate Copyright © 2015 Maria Antònia Busquets et al. All rights reserved. Impact of Depression, Fatigue, and Global Measure of Cortical Volume on Cognitive Impairment in Multiple Sclerosis Wed, 11 Mar 2015 11:53:36 +0000 Objective. To investigate the influence of demographic and clinical variables, such as depression, fatigue, and quantitative MRI marker on cognitive performances in a sample of patients affected by multiple sclerosis (MS). Methods. 60 MS patients (52 relapsing remitting and 8 primary progressive) underwent neuropsychological assessments using Rao’s Brief Repeatable Battery of Neuropsychological Tests (BRB-N), the Beck Depression Inventory-second edition (BDI-II), and the Fatigue Severity Scale (FSS). We performed magnetic resonance imaging to all subjects using a 3 T scanner and obtained tissue-specific volumes (normalized brain volume and cortical brain volume). We used Student’s t-test to compare depressed and nondepressed MS patients. Finally, we performed a multivariate regression analysis in order to assess possible predictors of patients’ cognitive outcome among demographic and clinical variables. Results. 27.12% of the sample (16/59) was cognitively impaired, especially in tasks requiring attention and information processing speed. From between group comparison, we find that depressed patients had worse performances on BRB-N score, greater disability and disease duration, and brain volume decrease. According to multiple regression analysis, the BDI-II score was a significant predictor for most of the neuropsychological tests. Conclusions. Our findings suggest that the presence of depressive symptoms is an important determinant of cognitive performance in MS patients. Domenica Nunnari, Maria Cristina De Cola, Giangaetano D’Aleo, Carmela Rifici, Margherita Russo, Edoardo Sessa, Placido Bramanti, and Silvia Marino Copyright © 2015 Domenica Nunnari et al. All rights reserved. The Interplay between Synaptic Activity and Neuroligin Function in the CNS Mon, 09 Mar 2015 09:16:38 +0000 Neuroligins (NLs) are postsynaptic transmembrane cell-adhesion proteins that play a key role in the regulation of excitatory and inhibitory synapses. Previous in vitro and in vivo studies have suggested that NLs contribute to synapse formation and synaptic transmission. Consistent with their localization, NL1 and NL3 selectively affect excitatory synapses, whereas NL2 specifically affects inhibitory synapses. Deletions or mutations in NL genes have been found in patients with autism spectrum disorders or mental retardations, and mice harboring the reported NL deletions or mutations exhibit autism-related behaviors and synapse dysfunction. Conversely, synaptic activity can regulate the phosphorylation, expression, and cleavage of NLs, which, in turn, can influence synaptic activity. Thus, in clinical research, identifying the relationship between NLs and synapse function is critical. In this review, we primarily discuss how NLs and synaptic activity influence each other. Xiaoge Hu, Jian-hong Luo, and Junyu Xu Copyright © 2015 Xiaoge Hu et al. All rights reserved. Dexamethasone Enhanced Functional Recovery after Sciatic Nerve Crush Injury in Rats Mon, 09 Mar 2015 06:36:01 +0000 Dexamethasone is currently used for the treatment of peripheral nerve injury, but its mechanisms of action are not completely understood. Inflammation/immune response at the site of nerve lesion is known to be an essential trigger of the pathological changes that have a critical impact on nerve repair and regeneration. In this study, we observed the effects of various doses of dexamethasone on the functional recovery after sciatic nerve crush injury in a rat model. Motor functional recovery was monitored by walking track analysis and gastrocnemius muscle mass ratio. The myelinated axon number was counted by morphometric analysis. Rats administered dexamethasone by local intramuscular injection had a higher nerve function index value, increased gastrocnemius muscle mass ratio, reduced Wallerian degeneration severity, and enhanced regenerated myelinated nerve fibers. Immunohistochemical analysis was performed for CD3 expression, which is a marker for T-cell activation, and infiltration in the sciatic nerve. Dexamethasone-injected rats had fewer CD3-positive cells compared to controls. Furthermore, we found increased expression of GAP-43, which is a factor associated with development and plasticity of the nervous system, in rat nerves receiving dexamethasone. These results provide strong evidence that dexamethasone enhances sciatic nerve regeneration and function recovery in a rat model of sciatic nerve injury through immunosuppressive and potential neurotrophic effects. Xinhong Feng and Wei Yuan Copyright © 2015 Xinhong Feng and Wei Yuan. All rights reserved. Comparative Analysis of Classifiers for Developing an Adaptive Computer-Assisted EEG Analysis System for Diagnosing Epilepsy Thu, 05 Mar 2015 11:31:05 +0000 Computer-assisted analysis of electroencephalogram (EEG) has a tremendous potential to assist clinicians during the diagnosis of epilepsy. These systems are trained to classify the EEG based on the ground truth provided by the neurologists. So, there should be a mechanism in these systems, using which a system’s incorrect markings can be mentioned and the system should improve its classification by learning from them. We have developed a simple mechanism for neurologists to improve classification rate while encountering any false classification. This system is based on taking discrete wavelet transform (DWT) of the signals epochs which are then reduced using principal component analysis, and then they are fed into a classifier. After discussing our approach, we have shown the classification performance of three types of classifiers: support vector machine (SVM), quadratic discriminant analysis, and artificial neural network. We found SVM to be the best working classifier. Our work exhibits the importance and viability of a self-improving and user adapting computer-assisted EEG analysis system for diagnosing epilepsy which processes each channel exclusive to each other, along with the performance comparison of different machine learning techniques in the suggested system. Malik Anas Ahmad, Yasar Ayaz, Mohsin Jamil, Syed Omer Gillani, Muhammad Babar Rasheed, Muhammad Imran, Nadeem Ahmed Khan, Waqas Majeed, and Nadeem Javaid Copyright © 2015 Malik Anas Ahmad et al. All rights reserved. Expression of MMP-9 and VEGF in Meningiomas and Their Correlation with Peritumoral Brain Edema Tue, 03 Mar 2015 07:47:40 +0000 Meningiomas constitute up to 13% of all intracranial tumors. The predictive factors for meningioma have not been unambiguously defined; however some limited data suggest that the expression of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) may be associated with the presence of peritumoral brain edema (PTBE) and worse clinical outcome. The aim of this study was to analyze the expressions of MMP-9 and VEGF in a group of meningiomas of various grades and to study associations between these two markers and PTBE. The study included patients with supratentorial meningiomas. The patients were divided into low- (G1) and high-grade meningiomas (G2 and G3). PTBE was assessed on MRI. The expressions of VEGF and MMP-9 were determined immunohistochemically. The expression of MMP-9 was observed significantly more often in G3 meningiomas than in lower grade tumors. The presence of stage II or III PTBE was associated with a significant increase in MMP-9 expression. The expression of VEGF did not differ across the PTBE stages. Our findings point to a significant role of MMP-9 and VEGF in the pathogenesis of peritumoral brain edema in low- and high-grade meningiomas. Joanna Reszec, Adam Hermanowicz, Robert Rutkowski, Grzegorz Turek, Zenon Mariak, and Lech Chyczewski Copyright © 2015 Joanna Reszec et al. All rights reserved. The Role of Cingulate Cortex in Vicarious Pain Thu, 26 Feb 2015 11:37:16 +0000 Vicarious pain is defined as the observation of individuals in pain. There is growing neuroimaging evidence suggesting that the cingulate cortex plays a significant role in self-experienced pain processing. Yet, very few studies have directly tested the distinct functions of the cingulate cortex for vicarious pain. In this review, one EEG and eighteen neuroimaging studies reporting cingulate cortex activity during pain observation were discussed. The data indicate that there is overlapping neural activity in the cingulate cortex during self- and vicarious pain. Such activity may contribute to shared neural pain representations that permit inference of the affective state of individuals in pain, facilitating empathy. However, the exact location of neuronal populations in which activity overlaps or differs for self- and observed pain processing requires further confirmation. This review also discusses evidence suggesting differential functions of the cingulate cortex in cognitive, affective, and motor processing during empathy induction. While affective processing in the cingulate cortex during pain observation has been explored relatively more often, its attention and motor roles remain underresearched. Shedding light on the neural correlates of vicarious pain and corresponding empathy in healthy populations can provide neurobiological markers and intervention targets for empathic deficits found in various clinical disorders. Esther H. Yesudas and Tatia M. C. Lee Copyright © 2015 Esther H. Yesudas and Tatia M. C. Lee. All rights reserved. Simultaneous Channel and Feature Selection of Fused EEG Features Based on Sparse Group Lasso Tue, 24 Feb 2015 10:12:17 +0000 Feature extraction and classification of EEG signals are core parts of brain computer interfaces (BCIs). Due to the high dimension of the EEG feature vector, an effective feature selection algorithm has become an integral part of research studies. In this paper, we present a new method based on a wrapped Sparse Group Lasso for channel and feature selection of fused EEG signals. The high-dimensional fused features are firstly obtained, which include the power spectrum, time-domain statistics, AR model, and the wavelet coefficient features extracted from the preprocessed EEG signals. The wrapped channel and feature selection method is then applied, which uses the logistical regression model with Sparse Group Lasso penalized function. The model is fitted on the training data, and parameter estimation is obtained by modified blockwise coordinate descent and coordinate gradient descent method. The best parameters and feature subset are selected by using a 10-fold cross-validation. Finally, the test data is classified using the trained model. Compared with existing channel and feature selection methods, results show that the proposed method is more suitable, more stable, and faster for high-dimensional feature fusion. It can simultaneously achieve channel and feature selection with a lower error rate. The test accuracy on the data used from international BCI Competition IV reached 84.72%. Jin-Jia Wang, Fang Xue, and Hui Li Copyright © 2015 Jin-Jia Wang et al. All rights reserved. Postnatal Administration of Allopregnanolone Modifies Glutamate Release but Not BDNF Content in Striatum Samples of Rats Prenatally Exposed to Ethanol Sun, 22 Feb 2015 13:21:13 +0000 Ethanol consumption during pregnancy may induce profound changes in fetal CNS development. We postulate that some of the effects of ethanol on striatal glutamatergic transmission and neurotrophin expression could be modulated by allopregnanolone, a neurosteroid modulator of receptor activity. We describe the acute pharmacological effect of allopregnanolone (65 μg/kg, s.c.) administered to juvenile male rats (day 21 of age) on the corticostriatal glutamatergic pathway, in both control and prenatally ethanol-exposed rats (two ip injections of 2.9 g/kg in 24% v/v saline solution on gestational day 8). Prenatal ethanol administration decreased the K+-induced release of glutamate regarding the control group. Interestingly, this effect was reverted by allopregnanolone. Regarding BDNF, allopregnanolone decreases the content of this neurotrophic factor in the striatum of control groups. However, both ethanol alone and ethanol plus allopregnanolone treated animals did not show any change regarding control values. We suggest that prenatal ethanol exposure may produce an alteration of receptors which blocks the GABA agonist-like effect of allopregnanolone on rapid glutamate release, thus disturbing normal neural transmission. Furthermore, the reciprocal interactions found between GABAergic neurosteroids and BDNF could underlie mechanisms operating during the neuronal plasticity of fetal development. Roberto Yunes, Cecilia R. Estrella, Sebastián García, Hernán E. Lara, and Ricardo Cabrera Copyright © 2015 Roberto Yunes et al. All rights reserved. Effects of Chronic REM Sleep Restriction on D1 Receptor and Related Signal Pathways in Rat Prefrontal Cortex Sun, 22 Feb 2015 09:40:10 +0000 The prefrontal cortex (PFC) mediates cognitive function that is sensitive to disruption by sleep loss, and molecular mechanisms regulating neural dysfunction induced by chronic sleep restriction (CSR), particularly in the PFC, have yet to be completely understood. The aim of the present study was to investigate the effect of chronic REM sleep restriction (REM-CSR) on the D1 receptor (D1R) and key molecules in D1R’ signal pathways in PFC. We employed the modified multiple platform method to create the REM-CSR rat model. The ultrastructure of PFC was observed by electron microscopy. HPLC was performed to measure the DA level in PFC. The expressions of genes and proteins of related molecules were assayed by real-time PCR and Western blot, respectively. The general state and morphology of PFC in rats were changed by CSR, and DA level and the expression of D1R in PFC were markedly decreased (, ); the expression of phosphor-PKAcα was significantly lowered in CSR rats (). The present results suggested that the alteration of neuropathology and D1R expression in PFC may be associated with CSR induced cognitive dysfunction, and the PKA pathway of D1R may play an important role in the impairment of advanced neural function. Yan Han, Xiaosa Wen, Fei Rong, Xinmin Chen, Ruying Ouyang, Shuai Wu, Hua Nian, and Wenling Ma Copyright © 2015 Yan Han et al. All rights reserved. Corrigendum to “Neurogenesis and Increase in Differentiated Neural Cell Survival via Phosphorylation of Akt1 after Fluoxetine Treatment of Stem Cells” Mon, 16 Feb 2015 09:27:42 +0000 Anahita Rahmani, Danial Kheradmand, Peyman Keyhanvar, Alireza Shoae-Hassani, and Amir Darbandi-Azar Copyright © 2015 Anahita Rahmani et al. All rights reserved. A Comparative Evaluation of a Novel Vaccine in APP/PS1 Mouse Models of Alzheimer’s Disease Wed, 11 Feb 2015 11:59:48 +0000 Immunization against amyloid-beta-peptide (Aβ) has been widely investigated as a potential immunotherapeutic approach for Alzheimer’s disease (AD). With the aim of developing an active immunogenic vaccine without need of coadjuvant modification for human trials and therefore avoiding such side effects, we designed the Aβ1–42 vaccine (EB101), delivered in a liposomal matrix, that based on our previous studies significantly prevents and reverses the AD neuropathology, clearing Aβ plaques while markedly reducing neuronal degeneration, behavioral deficits, and minimizing neuroinflammation in APP/PS1 transgenic mice. Here, the efficacy of our immunogenic vaccine EB101 was compared with the original immunization vaccine cocktail Aβ42 + CFA/IFA (Freund’s adjuvant), in order to characterize the effect of sphingosine-1-phosphate (S1P) in the immunotherapeutic response. Quantitative analysis of amyloid burden showed a notable decrease in the neuroinflammation reaction against Aβ plaques when S1P was compared with other treatments, suggesting that S1P plays a key role as a neuroprotective agent. Moreover, EB101 immunized mice presented a protective immunogenic reaction resulting in the increase of Aβ-specific antibody response and decrease of reactive glia in the affected brain areas, leading to a Th2 immunological reaction. Iván Carrera, Ignacio Etcheverría, Lucía Fernández-Novoa, Valter Ruggero Maria Lombardi, Madepalli Krishnappa Lakshmana, Ramón Cacabelos, and Carmen Vigo Copyright © 2015 Iván Carrera et al. All rights reserved. The Cell Birth Marker BrdU Does Not Affect Recruitment of Subsequent Cell Divisions in the Adult Avian Brain Wed, 11 Feb 2015 06:17:00 +0000 BrdU is commonly used to quantify neurogenesis but also causes mutation and has mitogenic, transcriptional, and translational effects. In mammalian studies, attention had been given to its dosage, but in birds such examination was not conducted. Our previous study suggested that BrdU might affect subsequent cell divisions and neuronal recruitment in the brain. Furthermore, this effect seemed to increase with time from treatment. Accordingly, we examined whether BrdU might alter neurogenesis in the adult avian brain. We compared recruitment of [3H]-thymidine+ neurons in brains of zebra finches (Taeniopygia guttata) when no BrdU was involved and when BrdU was given 1 or 3 months prior to [3H]-thymidine. In nidopallium caudale, HVC, and hippocampus, no differences were found between groups in densities and percentages of [3H]-thymidine+ neurons. The number of silver grains per [3H]-thymidine+ neuronal nucleus and their distribution were similar across groups. Additionally, time did not affect the results. The results indicate that the commonly used dosage of BrdU in birds has no long-term effects on subsequent cell divisions and neuronal recruitment. This conclusion is also important in neuronal replacement experiments, where BrdU and another cell birth marker are given, with relatively long intervals between them. Anat Cattan, Amir Ayali, and Anat Barnea Copyright © 2015 Anat Cattan et al. All rights reserved. The Interplay between Cyclic AMP, MAPK, and NF-κB Pathways in Response to Proinflammatory Signals in Microglia Thu, 05 Feb 2015 09:20:40 +0000 Cyclic AMP is an important intracellular regulator of microglial cell homeostasis and its negative perturbation through proinflammatory signaling results in microglial cell activation. Though cytokines, TNF-α and IL-1β, decrease intracellular cyclic AMP, the mechanism by which this occurs is poorly understood. The current study examined which signaling pathways are responsible for decreasing cyclic AMP in microglia following TNF-α stimulation and sought to identify the role cyclic AMP plays in regulating these pathways. In EOC2 microglia, TNF-α produced a dramatic reduction in cyclic AMP and increased cyclic AMP-dependent PDE activity that could be antagonized by Rolipram, myristoylated-PKI, PD98059, or JSH-23, implicating a role for PDE4, PKA, MEK, and NF-κB in this regulation. Following TNF-α there were significant increases in iNOS and COX-2 immunoreactivity, phosphorylated ERK1/2 and NF-κB-p65, IκB degradation, and NF-κB p65 nuclear translocation, which were reduced in the presence of high levels of cyclic AMP, indicating that reductions in cyclic AMP during cytokine stimulation are important for removing its inhibitory action on NF-κB activation and subsequent proinflammatory gene expression. Further elucidation of the signaling crosstalk involved in decreasing cyclic AMP in response to inflammatory signals may provide novel therapeutic targets for modulating microglial cell activation during neurological injury and disease. Mousumi Ghosh, Vladimir Aguirre, Khine Wai, Hady Felfly, W. Dalton Dietrich, and Damien D. Pearse Copyright © 2015 Mousumi Ghosh et al. All rights reserved. Disturbance of Oligodendrocyte Function Plays a Key Role in the Pathogenesis of Schizophrenia and Major Depressive Disorder Sun, 01 Feb 2015 13:22:29 +0000 The major psychiatric disorders such as schizophrenia (SZ) and major depressive disorder (MDD) are thought to be multifactorial diseases related to both genetic and environmental factors. However, the genes responsible and the molecular mechanisms underlying the pathogenesis of SZ and MDD remain unclear. We previously reported that abnormalities of disrupted-in-Schizophrenia-1 (DISC1) and DISC1 binding zinc finger (DBZ) might cause major psychiatric disorders such as SZ. Interestingly, both DISC and DBZ have been further detected in oligodendrocytes and implicated in regulating oligodendrocyte differentiation. DISC1 negatively regulates the differentiation of oligodendrocytes, whereas DBZ plays a positive regulatory role in oligodendrocyte differentiation. We have reported that repeated stressful events, one of the major risk factors of MDD, can induce sustained upregulation of plasma corticosterone levels and serum/glucocorticoid regulated kinase 1 (Sgk1) mRNA expression in oligodendrocytes. Repeated stressful events can also activate the SGK1 cascade and cause excess arborization of oligodendrocyte processes, which is thought to be related to depressive-like symptoms. In this review, we discuss the expression of DISC1, DBZ, and SGK1 in oligodendrocytes, their roles in the regulation of oligodendrocyte function, possible interactions of DISC1 and DBZ in relation to SZ, and the activation of the SGK1 signaling cascade in relation to MDD. Shingo Miyata, Tsuyoshi Hattori, Shoko Shimizu, Akira Ito, and Masaya Tohyama Copyright © 2015 Shingo Miyata et al. All rights reserved. The Protective Effect of Melatonin on Neural Stem Cell against LPS-Induced Inflammation Sun, 01 Feb 2015 12:07:47 +0000 Stem cell therapy for tissue regeneration has several limitations in the fact that transplanted cells could not survive for a long time. For solving these limitations, many studies have focused on the antioxidants to increase survival rate of neural stem cells (NSCs). Melatonin, an antioxidant synthesized in the pineal gland, plays multiple roles in various physiological mechanisms. Melatonin exerts neuroprotective effects in the central nervous system. To determine the effect of melatonin on NSCs which is in LPS-induced inflammatory stress state, we first investigated nitric oxide (NO) production and cytotoxicity using Griess reagent assays, LDH assay, and neurosphere counting. Also, we investigated the effect of melatonin on NSCs by measuring the mRNA levels of SOX2, TLX, and FGFR-2. In addition, western blot analyses were performed to examine the activation of PI3K/Akt/Nrf2 signaling in LPS-treated NSCs. In the present study, we suggested that melatonin inhibits NO production and protects NSCs against LPS-induced inflammatory stress. In addition, melatonin promoted the expression of SOX2 and activated the PI3K/Akt/Nrf2 signaling under LPS-induced inflammation condition. Based on our results, we conclude that melatonin may be an important factor for the survival and proliferation of NSCs in neuroinflammatory diseases. Juhyun Song, So Mang Kang, Kyoung Min Lee, and Jong Eun Lee Copyright © 2015 Juhyun Song et al. All rights reserved. Automatic Epileptic Seizure Detection Using Scalp EEG and Advanced Artificial Intelligence Techniques Thu, 29 Jan 2015 14:14:48 +0000 The epilepsies are a heterogeneous group of neurological disorders and syndromes characterised by recurrent, involuntary, paroxysmal seizure activity, which is often associated with a clinicoelectrical correlate on the electroencephalogram. The diagnosis of epilepsy is usually made by a neurologist but can be difficult to be made in the early stages. Supporting paraclinical evidence obtained from magnetic resonance imaging and electroencephalography may enable clinicians to make a diagnosis of epilepsy and investigate treatment earlier. However, electroencephalogram capture and interpretation are time consuming and can be expensive due to the need for trained specialists to perform the interpretation. Automated detection of correlates of seizure activity may be a solution. In this paper, we present a supervised machine learning approach that classifies seizure and nonseizure records using an open dataset containing 342 records. Our results show an improvement on existing studies by as much as 10% in most cases with a sensitivity of 93%, specificity of 94%, and area under the curve of 98% with a 6% global error using a k-class nearest neighbour classifier. We propose that such an approach could have clinical applications in the investigation of patients with suspected seizure disorders. Paul Fergus, David Hignett, Abir Hussain, Dhiya Al-Jumeily, and Khaled Abdel-Aziz Copyright © 2015 Paul Fergus et al. All rights reserved. An Expedient Synthesis, Acetylcholinesterase Inhibitory Activity, and Molecular Modeling Study of Highly Functionalized Hexahydro-1,6-naphthyridines Thu, 29 Jan 2015 07:33:10 +0000 A series of hexahydro-1,6-naphthyridines were synthesized in good yields by the reaction of 3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones with cyanoacetamide in the presence of sodium ethoxide under simple mixing at ambient temperature for 6–10 minutes and were assayed for their acetylcholinesterase (AChE) inhibitory activity using colorimetric Ellman’s method. Compound 4e with methoxy substituent at ortho-position of the phenyl rings displayed the maximum inhibitory activity with IC50 value of 2.12 μM. Molecular modeling simulation of 4e was performed using three-dimensional structure of Torpedo californica AChE (TcAChE) enzyme to disclose binding interaction and orientation of this molecule into the active site gorge of the receptor. Abdulrahman I. Almansour, Raju Suresh Kumar, Natarajan Arumugam, Alireza Basiri, Yalda Kia, and Mohamed Ashraf Ali Copyright © 2015 Abdulrahman I. Almansour et al. All rights reserved. Key Proteins of Activating Cell Death Can Be Predicted through a Kainic Acid-Induced Excitotoxic Stress Wed, 28 Jan 2015 11:45:07 +0000 Epilepsy is a major neurological disorder characterized by spontaneous seizures accompanied by neurophysiological changes. Repeated seizures can damage the brain as neuronal death occurs. A better understanding of the mechanisms of brain cell death could facilitate the discovery of novel treatments for neurological disorders such as epilepsy. In this study, a model of kainic acid- (KA-) induced neuronal death was established to investigate the early protein markers associated with apoptotic cell death due to excitotoxic damage in the rat cortex. The results indicated that KA induces both apoptotic and necrotic cell death in the cortex. Incubation with high concentrations (5 and 500 μM, >75%) and low concentrations (0.5 pM: 95% and 50 nM: 8%) of KA for 180 min led to necrotic and apoptotic cell death, respectively. Moreover, proteomic analysis using two-dimensional gel electrophoresis and mass spectrometry demonstrated that antiapoptotic proteins, including heat shock protein 70, 3-mercaptopyruvate sulfurtransferase, tubulin-B-5, and pyruvate dehydrogenase E1 component subunit beta, were significantly higher in apoptosis than in necrosis induced by KA. Our findings provide direct evidence that several proteins are associated with apoptotic and necrotic cell death in excitotoxicity model. The results indicate that these proteins can be apoptotic biomarkers from the early stages of cell death. Hsiu-Ling Tsai and Sue-Joan Chang Copyright © 2015 Hsiu-Ling Tsai and Sue-Joan Chang. All rights reserved. Acupuncture May Exert Its Therapeutic Effect through MicroRNA-339/Sirt2/NFB/FOXO1 Axis Wed, 28 Jan 2015 06:47:18 +0000 Recently, we have found that a number of microRNAs (miRNAs) and proteins are involved in the response to acupuncture therapy in hypertensive rats. Our bioinformatics study suggests an association between these miRNAs and proteins, which include miR-339 and sirtuin 2 (Sirt2). In this paper, we aimed to investigate whether Sirt2 was a direct target of miR-339 in neurons. In human SH-SY5Y cells, the luciferase assay implied that Sirt2 was likely a target of miRNA-339. Overexpression of miR-339 downregulated Sirt2 expression, while knockdown of miR-339 upregulated Sirt2 expression in human SH-SY5Y cells and rat PC12 cells. In addition, overexpression of miR-399 increased the acetylation of nuclear factor-B (NF-B) and forkhead box protein O1 (FOXO1) in SH-SY5Y cells, which are known targets of Sirt2. Our findings demonstrate that miR-339 regulates Sirt2 in human and rat neurons. Since Sirt2 plays a critical role in multiple important cellular functions, our data imply that acupuncture may act through epigenetic changes and subsequent action on their targets, such as miRNA-339/Sirt2/NF-B/FOXO1 axis. Some physiological level changes of neurons after altering the miR-339 levels are needed to validate the suggested therapeutic role of miR-339/Sirt2/NF-B/FOXO1 axis in response to acupuncture therapy in the future work. Jia-You Wang, Hui Li, Chun-Mei Ma, Jia-Lu Wang, Xin-Sheng Lai, and Shu-Feng Zhou Copyright © 2015 Jia-You Wang et al. All rights reserved. Neurodegeneration: Etiologies and New Therapies Thu, 22 Jan 2015 06:59:45 +0000 E. K. Tan, Amit K. Srivastava, W. David Arnold, Mahendra P. Singh, and Yiying Zhang Copyright © 2015 E. K. Tan et al. All rights reserved. Integrating Retrogenesis Theory to Alzheimer’s Disease Pathology: Insight from DTI-TBSS Investigation of the White Matter Microstructural Integrity Tue, 20 Jan 2015 11:57:37 +0000 Microstructural abnormalities in white matter (WM) are often reported in Alzheimer’s disease (AD) and may reflect primary or secondary circuitry degeneration (i.e., due to cortical atrophy). The interpretation of diffusion tensor imaging (DTI) eigenvectors, known as multiple indices, may provide new insights into the main pathological models supporting primary or secondary patterns of WM disruption in AD, the retrogenesis, and Wallerian degeneration models, respectively. The aim of this review is to analyze the current literature on the contribution of DTI multiple indices to the understanding of AD neuropathology, taking the retrogenesis model as a reference for discussion. A systematic review using MEDLINE, EMBASE, and PUBMED was performed. Evidence suggests that AD evolves through distinct patterns of WM disruption, in which retrogenesis or, alternatively, the Wallerian degeneration may prevail. Distinct patterns of WM atrophy may be influenced by complex interactions which comprise disease status and progression, fiber localization, concurrent risk factors (i.e., vascular disease, gender), and cognitive reserve. The use of DTI multiple indices in addition to other standard multimodal methods in dementia research may help to determine the contribution of retrogenesis hypothesis to the understanding of neuropathological hallmarks that lead to AD. Gilberto Sousa Alves, Viola Oertel Knöchel, Christian Knöchel, André Férrer Carvalho, Johannes Pantel, Eliasz Engelhardt, and Jerson Laks Copyright © 2015 Gilberto Sousa Alves et al. All rights reserved. Seizure-Induced Oxidative Stress in Temporal Lobe Epilepsy Tue, 20 Jan 2015 11:32:50 +0000 An insult to the brain (such as the first seizure) causes excitotoxicity, neuroinflammation, and production of reactive oxygen/nitrogen species (ROS/RNS). ROS and RNS produced during status epilepticus (SE) overwhelm the mitochondrial natural antioxidant defense mechanism. This leads to mitochondrial dysfunction and damage to the mitochondrial DNA. This in turn affects synthesis of various enzyme complexes that are involved in electron transport chain. Resultant effects that occur during epileptogenesis include lipid peroxidation, reactive gliosis, hippocampal neurodegeneration, reorganization of neural networks, and hypersynchronicity. These factors predispose the brain to spontaneous recurrent seizures (SRS), which ultimately establish into temporal lobe epilepsy (TLE). This review discusses some of these issues. Though antiepileptic drugs (AEDs) are beneficial to control/suppress seizures, their long term usage has been shown to increase ROS/RNS in animal models and human patients. In established TLE, ROS/RNS are shown to be harmful as they can increase the susceptibility to SRS. Further, in this paper, we review briefly the data from animal models and human TLE patients on the adverse effects of antiepileptic medications and the plausible ameliorating effects of antioxidants as an adjunct therapy. Sreekanth Puttachary, Shaunik Sharma, Sara Stark, and Thimmasettappa Thippeswamy Copyright © 2015 Sreekanth Puttachary et al. All rights reserved. Alleviation of Kainic Acid-Induced Brain Barrier Dysfunction by 4-O-Methylhonokiol in In Vitro and In Vivo Models Tue, 20 Jan 2015 09:01:06 +0000 This experiment was designed to investigate whether 4-O-methylhonokiol (MH), a principal ingredient of Magnolia (M.) officinalis bark, alleviated acute intraperitoneal (i.p.) kainic acid- (KA-) induced brain blood barrier dysfunction (BBBD) via pathological examination and cytological analyses of the brain tissues of mice. KA (10–30 mg/kg) time- and dose-dependently increased the water content of brain tissues and induced edema and encephalopathy. However, pretreatment with MH (5 and 20 mg/kg, i.p.) significantly reduced the water content of the brain compared to that observed in the KA control group. Furthermore, MH significantly and dose-dependently reversed the remarkable variations in evan’s blue dye (EBD) staining and malondialdehyde (MDA) levels that were induced by KA (10 mg/kg, i.p.). MH also decreased the elevated seizure scores that were induced by KA (10 mg/kg, i.p.) in mice in a manner similar to scavengers such as DMTU and trolox. Additionally, MH significantly scavenged intracellular ROS and Ca2+ within hippocampal cells. The tight junction seals mediated by claudin (Cld-5) were also found to be modulated by MH. MH efficiently reduced 1,1-diphenyl-2-picrylhydrazyl (DPPH) (IC50, 52.4 mM) and •OH with an electron spin resonance (ESR) signal rate constant of , which is close to the reactivity of the vitamin E analog trolox. Taken together, these results suggest that MH may enhance radical scavenging in lipid and hydrophobic environments, which may be important for the physiological activity of the barrier. Jin-Yi Han, Sun-Young Ahn, Jae Hyeon Yoo, Sang-Yoon Nam, Jin Tae Hong, and Ki-Wan Oh Copyright © 2015 Jin-Yi Han et al. All rights reserved. Dietary Factors in the Etiology of Parkinson’s Disease Tue, 20 Jan 2015 08:48:59 +0000 Parkinson’s disease (PD) is the second most common neurodegenerative disorder. The majority of cases do not arise from purely genetic factors, implicating an important role of environmental factors in disease pathogenesis. Well-established environmental toxins important in PD include pesticides, herbicides, and heavy metals. However, many toxicants linked to PD and used in animal models are rarely encountered. In this context, other factors such as dietary components may represent daily exposures and have gained attention as disease modifiers. Several in vitro, in vivo, and human epidemiological studies have found a variety of dietary factors that modify PD risk. Here, we critically review findings on association between dietary factors, including vitamins, flavonoids, calorie intake, caffeine, alcohol, and metals consumed via food and fatty acids and PD. We have also discussed key data on heterocyclic amines that are produced in high-temperature cooked meat, which is a new emerging field in the assessment of dietary factors in neurological diseases. While more research is clearly needed, significant evidence exists that specific dietary factors can modify PD risk. Zeynep S. Agim and Jason R. Cannon Copyright © 2015 Zeynep S. Agim and Jason R. Cannon. All rights reserved. Assessment of Hyperactive Reflexes in Patients with Spinal Cord Injury Thu, 15 Jan 2015 06:35:09 +0000 Hyperactive reflexes are commonly observed in patients with spinal cord injury (SCI) but there is a lack of convenient and quantitative characterizations. Patellar tendon reflexes were examined in nine SCI patients and ten healthy control subjects by tapping the tendon using a hand-held instrumented hammer at various knee flexion angles, and the tapping force, quadriceps EMG, and knee extension torque were measured to characterize patellar tendon reflexes quantitatively in terms of the tendon reflex gain (), contraction rate (), and reflex loop time delay (). It was found that there are significant increases in and and decrease in in patients with spinal cord injury as compared to the controls (). This study presented a convenient and quantitative method to evaluate reflex excitability and muscle contraction dynamics. With proper simplifications, it can potentially be used for quantitative diagnosis and outcome evaluations of hyperreflexia in clinical settings. Dali Xu, Xin Guo, Chung-Yong Yang, and Li-Qun Zhang Copyright © 2015 Dali Xu et al. All rights reserved. Balance Dysfunction in Parkinson’s Disease Wed, 14 Jan 2015 14:18:03 +0000 Stability and mobility in functional motor activities depend on a precise regulation of phasic and tonic muscular activity that is carried out automatically, without conscious awareness. The sensorimotor control of posture involves a complex integration of multisensory inputs that results in a final motor adjustment process. All or some of the components of this system may be dysfunctional in Parkinsonian patients, rendering postural instability one of the most disabling features of Parkinson’s disease (PD). Balance control is critical for moving safely in and adapting to the environment. PD induces a multilevel impairment of this function, therefore worsening the patients’ physical and psychosocial disability. In this review, we describe the complex ways in which PD impairs posture and balance, collecting and reviewing the available experimental evidence. Steno Rinalduzzi, Carlo Trompetto, Lucio Marinelli, Alessia Alibardi, Paolo Missori, Francesco Fattapposta, Francesco Pierelli, and Antonio Currà Copyright © 2015 Steno Rinalduzzi et al. All rights reserved. Spasticity and Its Contribution to Hypertonia in Cerebral Palsy Sun, 11 Jan 2015 11:31:35 +0000 Spasticity is considered an important neural contributor to muscle hypertonia in children with cerebral palsy (CP). It is most often treated with antispasticity medication, such as Botulinum Toxin-A. However, treatment response is highly variable. Part of this variability may be due to the inability of clinical tests to differentiate between the neural (e.g., spasticity) and nonneural (e.g., soft tissue properties) contributions to hypertonia, leading to the terms “spasticity” and “hypertonia” often being used interchangeably. Recent advancements in instrumented spasticity assessments offer objective measurement methods for distinction and quantification of hypertonia components. These methods can be applied in clinical settings and their results used to fine-tune and improve treatment. We reviewed current advancements and new insights with respect to quantifying spasticity and its contribution to muscle hypertonia in children with CP. First, we revisit what is known about spasticity in children with CP, including the various definitions and its pathophysiology. Second, we summarize the state of the art on instrumented spasticity assessment in CP and review the parameters developed to quantify the neural and nonneural components of hypertonia. Lastly, the impact these quantitative parameters have on clinical decision-making is considered and recommendations for future clinical and research investigations are discussed. Lynn Bar-On, Guy Molenaers, Erwin Aertbeliën, Anja Van Campenhout, Hilde Feys, Bart Nuttin, and Kaat Desloovere Copyright © 2015 Lynn Bar-On et al. All rights reserved. Electrophysiological Correlates of Long-Term Soto Zen Meditation Tue, 06 Jan 2015 11:25:39 +0000 This study aimed to verify the electrophysiological correlates of the changes in long-term regular meditators. We use modern techniques of high-resolution electroencephalography applied to slow potentials, power spectra, and potencies related to the events. To obtain encephalographic records, we use an assembly of 128 channels in 31 subjects (17 Soto Zen Buddhist meditators). The motivation of this study was to determine whether the induced beta power would present an increase in meditators as well as a decrease in induced theta/beta ratio in absolute and relative values. However, opposite to what we expected, no significant change was found in the beta frequency. In contrast, the main findings of the study were correlations between the frequency of weekly meditation practice and the increased theta induced relative power, increase of induced power ratio (ratio theta/beta), and increase of the ratio of induced relative powers (theta/beta ratio) during our task that featured an “adapted meditation,” suggesting that the meditative state of “mindfulness” is much more related to the permittivity of “distractions” by the meditators, with a deliberate reduction of attention. Henrique Adam Pasquini, Guaraci Ken Tanaka, Luis Fernando Hindi Basile, Bruna Velasques, Mirna Delposo Lozano, and Pedro Ribeiro Copyright © 2015 Henrique Adam Pasquini et al. All rights reserved. Riluzole Stimulates BDNF Release from Human Platelets Tue, 06 Jan 2015 06:31:34 +0000 Brain-derived neurotrophic factor (BDNF) has several functions in the central nervous system, where it contributes to brain development and its functionality through affecting neuronal survival and activity and also modulating neurotransmitter levels. This neurotrophin is also found in the serum, but its origin and peripheral function remain unknown. Although the source of circulating BDNF is uncertain, it is stored in platelets and can be released through pharmacological treatment. Decreased levels of BDNF in the serum have been related to the pathophysiology of depression, and this relationship is reinforced by the reversal of this condition by treatment with antidepressants. Recently, riluzole has been proposed for the treatment of depression because it has the ability to lower extracellular glutamate levels and increase BDNF expression; and both mechanisms could be associated with its antidepressant action. Considering that riluzole enhances BDNF levels in the serum of patients, we investigated if treatment with this drug could stimulate the release of this neurotrophin from human platelets obtained from healthy subjects. When platelets were incubated with riluzole for 4 h, the basal value of BDNF ( pg 10−6 platelets) was significantly increased (, ). This stimulatory effect was achieved at low concentrations of riluzole (from 10 µM) and was not observed when platelets were incubated with the drug for 24 h. The direct action of riluzole evoking BDNF release from human platelets at therapeutic concentrations is important and may contribute to the understanding of its mechanisms of action in the treatment of depression. Patrick Türck and Marcos Emílio Frizzo Copyright © 2015 Patrick Türck and Marcos Emílio Frizzo. All rights reserved. D-Aspartate Modulates Nociceptive-Specific Neuron Activity and Pain Threshold in Inflammatory and Neuropathic Pain Condition in Mice Mon, 05 Jan 2015 13:55:12 +0000 D-Aspartate (D-Asp) is a free D-amino acid found in the mammalian brain with a temporal-dependent concentration based on the postnatal expression of its metabolizing enzyme D-aspartate oxidase (DDO). D-Asp acts as an agonist on NMDA receptors (NMDARs). Accordingly, high levels of D-Asp in knockout mice for Ddo gene (Ddo−/−) or in mice treated with D-Asp increase NMDAR-dependent processes. We have here evaluated in Ddo−/− mice the effect of high levels of free D-Asp on the long-term plastic changes along the nociceptive pathway occurring in chronic and acute pain condition. We found that Ddo−/− mice show an increased evoked activity of the nociceptive specific (NS) neurons of the dorsal horn of the spinal cord (L4–L6) and a significant decrease of mechanical and thermal thresholds, as compared to control mice. Moreover, Ddo gene deletion exacerbated the nocifensive responses in the formalin test and slightly reduced pain thresholds in neuropathic mice up to 7 days after chronic constriction injury. These findings suggest that the NMDAR agonist, D-Asp, may play a role in the regulation of NS neuron electrophysiological activity and behavioral responses in physiological and pathological pain conditions. Serena Boccella, Valentina Vacca, Francesco Errico, Sara Marinelli, Marta Squillace, Francesca Guida, Anna Di Maio, Daniela Vitucci, Enza Palazzo, Vito De Novellis, Sabatino Maione, Flaminia Pavone, and Alessandro Usiello Copyright © 2015 Serena Boccella et al. All rights reserved. Prokineticin 2 Upregulation in the Peripheral Nervous System Has a Major Role in Triggering and Maintaining Neuropathic Pain in the Chronic Constriction Injury Model Mon, 05 Jan 2015 07:16:21 +0000 The new chemokine Prokineticin 2 (PROK2) and its receptors (PKR1 and PKR2) have a role in inflammatory pain and immunomodulation. Here we identified PROK2 as a critical mediator of neuropathic pain in the chronic constriction injury (CCI) of the sciatic nerve in mice and demonstrated that blocking the prokineticin receptors with two PKR1-preferring antagonists (PC1 and PC7) reduces pain and nerve damage. PROK2 mRNA expression was upregulated in the injured nerve since day 3 post injury (dpi) and in the ipsilateral DRG since 6 dpi. PROK2 protein overexpression was evident in Schwann Cells, infiltrating macrophages and axons in the peripheral nerve and in the neuronal bodies and some satellite cells in the DRG. Therapeutic treatment of neuropathic mice with the PKR-antagonist, PC1, impaired the PROK2 upregulation and signalling. This fact, besides alleviating pain, brought down the burden of proinflammatory cytokines in the damaged nerve and prompted an anti-inflammatory repair program. Such a treatment also reduced intraneural oedema and axon degeneration as demonstrated by the physiological skin innervation and thickness conserved in CCI-PC1 mice. These findings suggest that PROK2 plays a crucial role in neuropathic pain and might represent a novel target of treatment for this disease. Roberta Lattanzi, Daniela Maftei, Veronica Marconi, Fulvio Florenzano, Silvia Franchi, Elisa Borsani, Luigi Fabrizio Rodella, Gianfranco Balboni, Severo Salvadori, Paola Sacerdote, and Lucia Negri Copyright © 2015 Roberta Lattanzi et al. All rights reserved. mTOR Kinase: A Possible Pharmacological Target in the Management of Chronic Pain Thu, 01 Jan 2015 11:47:21 +0000 Chronic pain represents a major public health problem worldwide. Current pharmacological treatments for chronic pain syndromes, including neuropathic pain, are only partially effective, with significant pain relief achieved in 40–60% of patients. Recent studies suggest that the mammalian target of rapamycin (mTOR) kinase and downstream effectors may be implicated in the development of chronic inflammatory, neuropathic, and cancer pain. The expression and activity of mTOR have been detected in peripheral and central regions involved in pain transmission. mTOR immunoreactivity was found in primary sensory axons, in dorsal root ganglia (DRG), and in dorsal horn neurons. This kinase is a master regulator of protein synthesis, and it is critically involved in the regulation of several neuronal functions, including the synaptic plasticity that is a major mechanism leading to the development of chronic pain. Enhanced activation of this pathway is present in different experimental models of chronic pain. Consistently, pharmacological inhibition of the kinase activity turned out to have significant antinociceptive effects in several experimental models of inflammatory and neuropathic pain. We will review the main evidence from animal and human studies supporting the hypothesis that mTOR may be a novel pharmacological target for the management of chronic pain. Lucia Lisi, Paola Aceto, Pierluigi Navarra, and Cinzia Dello Russo Copyright © 2015 Lucia Lisi et al. All rights reserved. Inflammatory Reaction in Neurological Diseases Wed, 31 Dec 2014 10:04:31 +0000 Hung-Chen Wang, Cheng-Hsien Lu, Kuang-I Cheng, and Jason Cheng-Hsuan Chiang Copyright © 2014 Hung-Chen Wang et al. All rights reserved. Peripheral Nerve Regeneration: Mechanism, Cell Biology, and Therapies Tue, 23 Dec 2014 06:40:03 +0000 Xiaofeng Jia, Mario I. Romero-Ortega, and Yang D. Teng Copyright © 2014 Xiaofeng Jia et al. All rights reserved. Different Resting-State Functional Connectivity Alterations in Smokers and Nonsmokers with Internet Gaming Addiction Tue, 18 Nov 2014 13:42:02 +0000 This study investigated changes in resting-state functional connectivity (rsFC) of posterior cingulate cortex (PCC) in smokers and nonsmokers with Internet gaming addiction (IGA). Twenty-nine smokers with IGA, 22 nonsmokers with IGA, and 30 healthy controls (HC group) underwent a resting-state fMRI scan. PCC connectivity was determined in all subjects by investigating synchronized low-frequency fMRI signal fluctuations using a temporal correlation method. Compared with the nonsmokers with IGA, the smokers with IGA exhibited decreased rsFC with PCC in the right rectus gyrus. Left middle frontal gyrus exhibited increased rsFC. The PCC connectivity with the right rectus gyrus was found to be negatively correlated with the CIAS scores in the smokers with IGA before correction. Our results suggested that smokers with IGA had functional changes in brain areas related to motivation and executive function compared with the nonsmokers with IGA. Xue Chen, Yao Wang, Yan Zhou, Yawen Sun, Weina Ding, Zhiguo Zhuang, Jianrong Xu, and Yasong Du Copyright © 2014 Xue Chen et al. All rights reserved. Neuroprotective Effects of Geniposide in SH-SY5Y Cells and Primary Hippocampal Neurons Exposed to Aβ42 Tue, 18 Nov 2014 09:37:50 +0000 Our former studies have suggested that TongLuoJiuNao (TLJN) is clinically efficacious in the treatment of dementia and improving learning and memory in AD models. When Aβ aggregated with oligomer, it is known to be able to induce cellular toxicity as well as cognitive impairment. We tested the possibility that TLJN affects the formation of Aβ oligomers. In our experiment, TLJN improved cell viability, inhibited LDH release, and promoted the outgrowth of neurites of neurons treated with Aβ. Geniposide, the main component of TLJN, could increase the cell viability of SY5Y-APP695sw cells. The cytotoxicity of pretreated Aβ with geniposide was decreased in a dose-dependent manner. SDS-PAGE and Western blotting showed that geniposide and TLJN stimulated Aβ oligomer assembly. Compared with the control, more and longer fibrils of Aβ in the presence of geniposide were observed under electron microscope though the fibrils became less sensitive to thioflavin T staining. In sum, geniposide is able to protect neurons from Aβ-induced damage by remodeling Aβ. Ping Sun, Haimin Ding, Mi Liang, Xiaojing Li, Weichuan Mo, Xu Wang, Ying Liu, Rongqiao He, and Qian Hua Copyright © 2014 Ping Sun et al. All rights reserved. Inhibition of Brain Swelling after Ischemia-Reperfusion by β-Adrenergic Antagonists: Correlation with Increased K+ and Decreased Ca2+ Concentrations in Extracellular Fluid Thu, 13 Nov 2014 12:18:28 +0000 Infarct size and brain edema following ischemia/reperfusion are reduced by inhibitors of the Na+, K+, 2Cl−, and water cotransporter NKCC1 and by β1-adrenoceptor antagonists. NKCC1 is a secondary active transporter, mainly localized in astrocytes, driven by transmembrane Na+/K+ gradients generated by the Na+,K+-ATPase. The astrocytic Na+,K+-ATPase is stimulated by small increases in extracellular K+ concentration and by the β-adrenergic agonist isoproterenol. Larger K+ increases, as occurring during ischemia, also stimulate NKCC1, creating cell swelling. This study showed no edema after 3 hr medial cerebral artery occlusion but pronounced edema after 8 hr reperfusion. The edema was abolished by inhibitors of specifically β1-adrenergic pathways, indicating failure of K+-mediated, but not β1-adrenoceptor-mediated, stimulation of Na+,K+-ATPase/NKCC1 transport during reoxygenation. Ninety percent reduction of extracellular Ca2+ concentration occurs in ischemia. Ca2+ omission abolished K+ uptake in normoxic cultures of astrocytes after addition of 5 mM KCl. A large decrease in ouabain potency on K+ uptake in cultured astrocytes was also demonstrated in Ca2+-depleted media, and endogenous ouabains are needed for astrocytic K+ uptake. Thus, among the ionic changes induced by ischemia, the decrease in extracellular Ca2+ causes failure of the high-K+-stimulated Na+,K+-ATPase/NKCC1 ion/water uptake, making β1-adrenergic activation the only stimulus and its inhibition effective against edema. Dan Song, Junnan Xu, Ting Du, Enzhi Yan, Leif Hertz, Wolfgang Walz, and Liang Peng Copyright © 2014 Dan Song et al. All rights reserved. Pathophysiology of Spasticity: Implications for Neurorehabilitation Thu, 30 Oct 2014 07:11:25 +0000 Spasticity is the velocity-dependent increase in muscle tone due to the exaggeration of stretch reflex. It is only one of the several components of the upper motor neuron syndrome (UMNS). The central lesion causing the UMNS disrupts the balance of supraspinal inhibitory and excitatory inputs directed to the spinal cord, leading to a state of disinhibition of the stretch reflex. However, the delay between the acute neurological insult (trauma or stroke) and the appearance of spasticity argues against it simply being a release phenomenon and suggests some sort of plastic changes, occurring in the spinal cord and also in the brain. An important plastic change in the spinal cord could be the progressive reduction of postactivation depression due to limb immobilization. As well as hyperexcitable stretch reflexes, secondary soft tissue changes in the paretic limbs enhance muscle resistance to passive displacements. Therefore, in patients with UMNS, hypertonia can be divided into two components: hypertonia mediated by the stretch reflex, which corresponds to spasticity, and hypertonia due to soft tissue changes, which is often referred as nonreflex hypertonia or intrinsic hypertonia. Compelling evidences state that limb mobilisation in patients with UMNS is essential to prevent and treat both spasticity and intrinsic hypertonia. Carlo Trompetto, Lucio Marinelli, Laura Mori, Elisa Pelosin, Antonio Currà, Luigi Molfetta, and Giovanni Abbruzzese Copyright © 2014 Carlo Trompetto et al. All rights reserved. Molecular Chaperone Dysfunction in Neurodegenerative Diseases and Effects of Curcumin Sun, 19 Oct 2014 08:23:16 +0000 The intra- and extracellular accumulation of misfolded and aggregated amyloid proteins is a common feature in several neurodegenerative diseases, which is thought to play a major role in disease severity and progression. The principal machineries maintaining proteostasis are the ubiquitin proteasomal and lysosomal autophagy systems, where heat shock proteins play a crucial role. Many protein aggregates are degraded by the lysosomes, depending on aggregate size, peptide sequence, and degree of misfolding, while others are selectively tagged for removal by heat shock proteins and degraded by either the proteasome or phagosomes. These systems are compromised in different neurodegenerative diseases. Therefore, developing novel targets and classes of therapeutic drugs, which can reduce aggregates and maintain proteostasis in the brains of neurodegenerative models, is vital. Natural products that can modulate heat shock proteins/proteosomal pathway are considered promising for treating neurodegenerative diseases. Here we discuss the current knowledge on the role of HSPs in protein misfolding diseases and knowledge gained from animal models of Alzheimer’s disease, tauopathies, and Huntington’s diseases. Further, we discuss the emerging treatment regimens for these diseases using natural products, like curcumin, which can augment expression or function of heat shock proteins in the cell. Panchanan Maiti, Jayeeta Manna, Shobi Veleri, and Sally Frautschy Copyright © 2014 Panchanan Maiti et al. All rights reserved. From Pathways to Targets: Understanding the Mechanisms behind Polyglutamine Disease Sun, 21 Sep 2014 06:05:06 +0000 The history of polyglutamine diseases dates back approximately 20 years to the discovery of a polyglutamine repeat in the androgen receptor of SBMA followed by the identification of similar expansion mutations in Huntington’s disease, SCA1, DRPLA, and the other spinocerebellar ataxias. This common molecular feature of polyglutamine diseases suggests shared mechanisms in disease pathology and neurodegeneration of disease specific brain regions. In this review, we discuss the main pathogenic pathways including proteolytic processing, nuclear shuttling and aggregation, mitochondrial dysfunction, and clearance of misfolded polyglutamine proteins and point out possible targets for treatment. Jonasz Jeremiasz Weber, Anna Sergeevna Sowa, Tina Binder, and Jeannette Hübener Copyright © 2014 Jonasz Jeremiasz Weber et al. All rights reserved. Myristic Acid Produces Anxiolytic-Like Effects in Wistar Rats in the Elevated Plus Maze Thu, 18 Sep 2014 12:23:46 +0000 A mixture of eight fatty acids (linoleic, palmitic, stearic, myristic, elaidic, lauric, oleic, and palmitoleic acids) at similar concentrations identified in human amniotic fluid produces anxiolytic-like effects comparable to diazepam in Wistar rats. However, individual effects of each fatty acid remain unexplored. In Wistar rats, we evaluated the separate action of each fatty acid at the corresponding concentrations previously found in human amniotic fluid on anxiety-like behaviour. Individual effects were compared with vehicle, an artificial mixture of the same eight fatty acids, and a reference anxiolytic drug (diazepam, 2 mg/kg). Myristic acid, the fatty acid mixture, and diazepam increased the time spent in the open arms of the elevated plus maze and reduced the anxiety index compared with vehicle, without altering general locomotor activity. The other fatty acids had no effect on anxiety-like behaviour, but oleic acid reduced locomotor activity. Additionally, myristic acid produced anxiolytic-like effects only when the concentration corresponded to the one identified in human amniotic fluid (30 𝜇g/mL) but did not alter locomotor activity. We conclude that of the eight fatty acids contained in the fatty acid mixture, only myristic acid produces anxiolytic-like effects when administered individually at a similar concentration detected in human amniotic fluid. Carlos M. Contreras, Juan Francisco Rodríguez-Landa, Rosa Isela García-Ríos, Jonathan Cueto-Escobedo, Gabriel Guillen-Ruiz, and Blandina Bernal-Morales Copyright © 2014 Carlos M. Contreras et al. All rights reserved. Shock Waves in the Treatment of Muscle Hypertonia and Dystonia Wed, 17 Sep 2014 00:00:00 +0000 Since 1997, focused shock waves therapy (FSWT) has been reported to be useful in the treatment of muscle hypertonia and dystonia. More recently, also radial shock wave therapy (RSWT) has been successfully used to treat muscle hypertonia. The studies where FSWT and RSWT have been used to treat muscle hypertonia and dystonia are reviewed in this paper. The more consistent and long lasting results were obtained in the lower limb muscles of patients affected by cerebral palsy with both FSWT and RSWT and in the distal upper limb muscles of adult stroke patients using FSWT. The most probable mechanism of action is a direct effect of shock waves on muscle fibrosis and other nonreflex components of muscle hypertonia. However, we believe that up to now the biological effects of shock waves on muscle hypertonia and dystonia cannot be clearly separated from a placebo effect. Laura Mori, Lucio Marinelli, Elisa Pelosin, Antonio Currà, Luigi Molfetta, Giovanni Abbruzzese, and Carlo Trompetto Copyright © 2014 Laura Mori et al. All rights reserved. Proteomic Identification of Altered Cerebral Proteins in the Complex Regional Pain Syndrome Animal Model Tue, 16 Sep 2014 09:15:56 +0000 Background. Complex regional pain syndrome (CRPS) is a rare but debilitating pain disorder. Although the exact pathophysiology of CRPS is not fully understood, central and peripheral mechanisms might be involved in the development of this disorder. To reveal the central mechanism of CRPS, we conducted a proteomic analysis of rat cerebrum using the chronic postischemia pain (CPIP) model, a novel experimental model of CRPS. Materials and Methods. After generating the CPIP animal model, we performed a proteomic analysis of the rat cerebrum using a multidimensional protein identification technology, and screened the proteins differentially expressed between the CPIP and control groups. Results. A total of 155 proteins were differentially expressed between the CPIP and control groups: 125 increased and 30 decreased; expressions of proteins related to cell signaling, synaptic plasticity, regulation of cell proliferation, and cytoskeletal formation were increased in the CPIP group. However, proenkephalin A, cereblon, and neuroserpin were decreased in CPIP group. Conclusion. Altered expression of cerebral proteins in the CPIP model indicates cerebral involvement in the pathogenesis of CRPS. Further study is required to elucidate the roles of these proteins in the development and maintenance of CRPS. Francis Sahngun Nahm, Zee-Yong Park, Sang-Soep Nahm, Yong Chul Kim, and Pyung Bok Lee Copyright © 2014 Francis Sahngun Nahm et al. All rights reserved. Synaptojanin 1 Mutation in Parkinson’s Disease Brings Further Insight into the Neuropathological Mechanisms Tue, 16 Sep 2014 05:40:45 +0000 Synaptojanin 1 (SYNJ1) is a phosphoinositide phosphatase highly expressed in nerve terminals. Its two phosphatase domains dephosphorylate phosphoinositides present in membranes, while its proline-rich domain directs protein-protein interactions with synaptic components, leading to efficient recycling of synaptic vesicles in neurons. Triplication of SYNJ1 in Down’s syndrome is responsible for higher level of phosphoinositides, enlarged endosomes, and learning deficits. SYNJ1 downregulation in Alzheimer’s disease models is protective towards amyloid-beta peptide (Aβ) toxicity. One missense mutation in one of SYNJ1 functional domains was recently incriminated in an autosomal recessive form of early-onset Parkinson’s disease (PD). In the third decade of life, these patients develop progressive Parkinsonism with bradykinesia, dystonia, and variable atypical symptoms such as cognitive decline, seizures, and eyelid apraxia. The identification of this new gene, together with the fact that most of the known PD proteins play a role in synaptic vesicle recycling and lipid metabolism, points out that synaptic maintenance is a key player in PD pathological mechanisms. Studying PD genes as a network regulating synaptic activity could bring insight into understanding the neuropathological processes of PD and help identify new genes at fault in this devastating disorder. Valérie Drouet and Suzanne Lesage Copyright © 2014 Valérie Drouet and Suzanne Lesage. All rights reserved. Magnetic Resonance Spectroscopy: An In Vivo Molecular Imaging Biomarker for Parkinson’s Disease? Thu, 11 Sep 2014 11:00:41 +0000 Parkinson’s disease (PD) is a neurodegenerative disorder caused by selective loss of dopaminergic neurons in the substantia nigra pars compacta which leads to dysfunction of cerebral pathways critical for the control of movements. The diagnosis of PD is based on motor symptoms, such as bradykinesia, akinesia, muscular rigidity, postural instability, and resting tremor, which are evident only after the degeneration of a significant number of dopaminergic neurons. Currently, a marker for early diagnosis of PD is still not available. Consequently, also the development of disease-modifying therapies is a challenge. Magnetic resonance spectroscopy is a quantitative imaging technique that allows in vivo measurement of certain neurometabolites and may produce biomarkers that reflect metabolic dysfunctions and irreversible neuronal damage. This review summarizes the abnormalities of cerebral metabolites found in MRS studies performed in patients with PD and other forms of parkinsonism. In addition, we discuss the potential role of MRS as in vivo molecular imaging biomarker for early diagnosis of PD and for monitoring the efficacy of therapeutic interventions. Rosella Ciurleo, Giuseppe Di Lorenzo, Placido Bramanti, and Silvia Marino Copyright © 2014 Rosella Ciurleo et al. All rights reserved. Translational Research in Peripheral Nerve Repair and Regeneration Tue, 09 Sep 2014 07:33:39 +0000 Nektarios Sinis, Stefano Geuna, and Fausto Viterbo Copyright © 2014 Nektarios Sinis et al. All rights reserved. Glatiramer Acetate and Nanny Proteins Restrict Access of the Multiple Sclerosis Autoantigen Myelin Basic Protein to the 26S Proteasome Mon, 08 Sep 2014 09:40:46 +0000 We recently showed that myelin basic protein (MBP) is hydrolyzed by 26S proteasome without ubiquitination. The previously suggested concept of charge-mediated interaction between MBP and the proteasome led us to attempt to compensate or mimic its positive charge to inhibit proteasomal degradation. We demonstrated that negatively charged actin and calmodulin (CaM), as well as basic histone H1.3, inhibit MBP hydrolysis by competing with the proteasome and MBP, respectively, for binding their counterpart. Interestingly, glatiramer acetate (GA), which is used to treat multiple sclerosis (MS) and is structurally similar to MBP, inhibits intracellular and in vitro proteasome-mediated MBP degradation. Therefore, the data reported in this study may be important for myelin biogenesis in both the normal state and pathophysiological conditions. Ekaterina Kuzina, Anna Kudriaeva, Ivan Smirnov, Michael V. Dubina, Alexander Gabibov, and Alexey Belogurov Jr. Copyright © 2014 Ekaterina Kuzina et al. All rights reserved. Reliability and Validity of the Nigerian (Hausa) Version of the Stroke Impact Scale (SIS) 3.0 Index Sun, 07 Sep 2014 11:12:16 +0000 This study aims to test the translated Hausa version of the stroke impact scale SIS (3.0) and further evaluate its psychometric properties. The SIS 3.0 was translated from English into Hausa and was tested for its reliability and validity on a stratified random sample adult stroke survivors attending rehabilitation services at stroke referral hospitals in Kano, Nigeria. Psychometric analysis of the Hausa-SIS 3.0 involved face, content, criterion, and construct validity tests as well as internal and test-retest reliability. In reliability analyses, the Cronbach’s alpha values for the items in Strength, Hand function, Mobility, ADL/IADL, Memory and thinking, Communication, Emotion, and Social participation domains were 0.80, 0.92, 0.90, 0.78, 0.84, 0.89, 0.58, and 0.74, respectively. There are 8 domains in stroke impact scale 3.0 in confirmatory factory analysis; some of the items in the Hausa-SIS questionnaire have to be dropped due to lack of discriminate validity. In the final analysis, a parsimonious model was obtained with two items per construct for the 8 constructs (Chi-square/df 3, TLI and CFI 0.9, and RMSEA 0.08). Cross validation with 1000 bootstrap samples gave a satisfactory result (P = 0.011). In conclusion, the shorter 16-item Hausa-SIS seems to measure adequately the QOL outcomes in the 8 domains. Ashiru Hamza Mohammad, Nabilla Al-Sadat, Loh Siew Yim, and Karuthan Chinna Copyright © 2014 Ashiru Hamza Mohammad et al. All rights reserved. The Purinergic System and Glial Cells: Emerging Costars in Nociception Wed, 03 Sep 2014 08:36:09 +0000 It is now well established that glial cells not only provide mechanical and trophic support to neurons but can directly contribute to neurotransmission, for example, by release and uptake of neurotransmitters and by secreting pro- and anti-inflammatory mediators. This has greatly changed our attitude towards acute and chronic disorders, paving the way for new therapeutic approaches targeting activated glial cells to indirectly modulate and/or restore neuronal functions. A deeper understanding of the molecular mechanisms and signaling pathways involved in neuron-to-glia and glia-to-glia communication that can be pharmacologically targeted is therefore a mandatory step toward the success of this new healing strategy. This holds true also in the field of pain transmission, where the key involvement of astrocytes and microglia in the central nervous system and satellite glial cells in peripheral ganglia has been clearly demonstrated, and literally hundreds of signaling molecules have been identified. Here, we shall focus on one emerging signaling system involved in the cross talk between neurons and glial cells, the purinergic system, consisting of extracellular nucleotides and nucleosides and their membrane receptors. Specifically, we shall summarize existing evidence of novel “druggable” glial purinergic targets, which could help in the development of innovative analgesic approaches to chronic pain states. Giulia Magni and Stefania Ceruti Copyright © 2014 Giulia Magni and Stefania Ceruti. All rights reserved. Minocycline Enhances the Effectiveness of Nociceptin/Orphanin FQ during Neuropathic Pain Wed, 03 Sep 2014 07:18:11 +0000 Nociceptin/orphanin FQ (N/OFQ) antinociception, which is mediated selectively by the N/OFQ peptide receptor (NOP), was demonstrated in pain models. In this study, we determine the role of activated microglia on the analgesic effects of N/OFQ in a rat model of neuropathic pain induced by chronic constriction injury (CCI) to the sciatic nerve. Repeated 7-day administration of minocycline (30 mg/kg i.p.), a drug that affects microglial activation, significantly reduced pain in CCI-exposed rats and it potentiates the analgesic effects of administered N/OFQ (2.5–5 μg i.t.). Minocycline also downregulates the nerve injury-induced upregulation of NOP protein in the dorsal lumbar spinal cord. Our in vitro study showed that minocycline reduced NOP mRNA, but not protein, level in rat primary microglial cell cultures. In [35S]GTPγS binding assays we have shown that minocycline increases the spinal N/OFQ-stimulated NOP signaling. We suggest that the modulation of the N/OFQ system by minocycline is due to the potentiation of its neuronal antinociceptive activity and weakening of the microglial cell activation. This effect is beneficial for pain relief, and these results suggest new targets for the development of drugs that are effective against neuropathic pain. Katarzyna Popiolek-Barczyk, Ewelina Rojewska, Agnieszka M. Jurga, Wioletta Makuch, Ferenz Zador, Anna Borsodi, Anna Piotrowska, Barbara Przewlocka, and Joanna Mika Copyright © 2014 Katarzyna Popiolek-Barczyk et al. All rights reserved. Peripheral Nerve Reconstruction after Injury: A Review of Clinical and Experimental Therapies Wed, 03 Sep 2014 07:04:39 +0000 Unlike other tissues in the body, peripheral nerve regeneration is slow and usually incomplete. Less than half of patients who undergo nerve repair after injury regain good to excellent motor or sensory function and current surgical techniques are similar to those described by Sunderland more than 60 years ago. Our increasing knowledge about nerve physiology and regeneration far outweighs our surgical abilities to reconstruct damaged nerves and successfully regenerate motor and sensory function. It is technically possible to reconstruct nerves at the fascicular level but not at the level of individual axons. Recent surgical options including nerve transfers demonstrate promise in improving outcomes for proximal nerve injuries and experimental molecular and bioengineering strategies are being developed to overcome biological roadblocks limiting patient recovery. D. Grinsell and C. P. Keating Copyright © 2014 D. Grinsell and C. P. Keating. All rights reserved. Decreased Fast Ripples in the Hippocampus of Rats with Spontaneous Recurrent Seizures Treated with Carbenoxolone and Quinine Wed, 03 Sep 2014 06:39:22 +0000 Background. In models of temporal lobe epilepsy and in patients with this pathology, high frequency oscillations called fast ripples (FRs, 250–600 Hz) can be observed. FRs are considered potential biomarkers for epilepsy and, in the light of many in vitro and in silico studies, we thought that electrical synapses mediated by gap junctions might possibly modulate FRs in vivo. Methods. Animals with spontaneous recurrent seizures induced by pilocarpine administration were implanted with movable microelectrodes in the right anterior and posterior hippocampus to evaluate the effects of gap junction blockers administered in the entorhinal cortex. The effects of carbenoxolone (50 nmoles) and quinine (35 pmoles) on the mean number of spontaneous FR events (occurrence of FRs), as well as on the mean number of oscillation cycles per FR event and their frequency, were assessed using a specific algorithm to analyze FRs in intracranial EEG recordings. Results. We found that these gap junction blockers decreased the mean number of FRs and the mean number of oscillation cycles per FR event in the hippocampus, both during and at different times after carbenoxolone and quinine administration. Conclusion. These data suggest that FRs may be modulated by gap junctions, although additional experiments in vivo will be necessary to determine the precise role of gap junctions in this pathological activity associated with epileptogenesis. Consuelo Ventura-Mejía and Laura Medina-Ceja Copyright © 2014 Consuelo Ventura-Mejía and Laura Medina-Ceja. All rights reserved. Remote Dose-Dependent Effects of Dry Needling at Distant Myofascial Trigger Spots of Rabbit Skeletal Muscles on Reduction of Substance P Levels of Proximal Muscle and Spinal Cords Wed, 03 Sep 2014 06:28:31 +0000 Background. Dry needling at distant myofascial trigger points is an effective pain management in patients with myofascial pain. However, the biochemical effects of remote dry needling are not well understood. This study evaluates the remote effects of dry needling with different dosages on the expressions of substance P (SP) in the proximal muscle, spinal dorsal horns of rabbits. Methods. Male New Zealand rabbits (2.5–3.0 kg) received dry needling at myofascial trigger spots of a gastrocnemius (distant muscle) in one (1D) or five sessions (5D). Bilateral biceps femoris (proximal muscles) and superficial laminaes of L5-S2, T2-T5, and C2-C5 were sampled immediately and 5 days after dry needling to determine the levels of SP using immunohistochemistry and western blot. Results. Immediately after dry needling for 1D and 5D, the expressions of SP were significantly decreased in ipsilateral biceps femoris and bilateral spinal superficial laminaes (). Five days after dry needling, these reduced immunoactivities of SP were found only in animals receiving 5D dry needling (). Conclusions. This remote effect of dry needling involves the reduction of SP levels in proximal muscle and spinal superficial laminaes, which may be closely associated with the control of myofascial pain. Yueh-Ling Hsieh, Chen-Chia Yang, Szu-Yu Liu, Li-Wei Chou, and Chang-Zern Hong Copyright © 2014 Yueh-Ling Hsieh et al. All rights reserved. Alterations in the Anandamide Metabolism in the Development of Neuropathic Pain Tue, 02 Sep 2014 13:20:59 +0000 Endocannabinoids (EC), particularly anandamide (AEA), released constitutively in pain pathways might be accountable for the inhibitory effect on nociceptors. Pathogenesis of neuropathic pain may reflect complex remodeling of the dorsal root ganglia (DRGs) and spinal cord EC system. Multiple pathways involved both in the biosynthesis and degradation of AEA have been suggested. We investigated the local synthesis and degradation features of AEA in DRGs and spinal cord during the development and maintenance of pain in a model of chronic constriction injury (CCI). All AEA synthesis and degradation enzymes are present on the mRNA level in DRGs and lumbar spinal cord of intact as well as CCI-treated animals. Deregulation of EC system components was consistent with development of pain phenotype at days 3, 7, and 14 after CCI. The expression levels of enzymes involved in AEA degradation was significantly upregulated ipsilateral in DRGs and spinal cord at different time points. Expression of enzymes of the alternative, sPLA2-dependent and PLC-dependent, AEA synthesis pathways was elevated in both of the analyzed structures at all time points. Our data have shown an alteration of alternative AEA synthesis and degradation pathways, which might contribute to the variation of AEA levels and neuropathic pain development. Natalia Malek, Mateusz Kucharczyk, and Katarzyna Starowicz Copyright © 2014 Natalia Malek et al. All rights reserved. MicroRNA Profiling Reveals Unique miRNA Signatures in IGF-1 Treated Embryonic Striatal Stem Cell Fate Decisions in Striatal Neurogenesis In Vitro Mon, 01 Sep 2014 08:22:06 +0000 The striatum is considered to be the central processing unit of the basal ganglia in locomotor activity and cognitive function of the brain. IGF-1 could act as a control switch for the long-term proliferation and survival of EGF + bFGF-responsive cultured embryonic striatal stem cell (ESSC), while LIF imposes a negative impact on cell proliferation. The IGF-1-treated ESSCs also showed elevated hTERT expression with demonstration of self-renewal and trilineage commitment (astrocytes, oligodendrocytes, and neurons). In order to decipher the underlying regulatory microRNA (miRNA)s in IGF-1/LIF-treated ESSC-derived neurogenesis, we performed in-depth miRNA profiling at 12 days in vitro and analyzed the candidates using the Partek Genome Suite software. The annotated miRNA fingerprints delineated the differential expressions of miR-143, miR-433, and miR-503 specific to IGF-1 treatment. Similarly, the LIF-treated ESSCs demonstrated specific expression of miR-326, miR-181, and miR-22, as they were nonsignificant in IGF-treated ESSCs. To elucidate the possible downstream pathways, we performed in silico mapping of the said miRNAs into ingenuity pathway analysis. Our findings revealed the important mRNA targets of the miRNAs and suggested specific interactomes. The above studies introduced a new genre of miRNAs for ESSC-based neuroregenerative therapeutic applications. Soumya Pati, Nor Entan Supeno, Sangu Muthuraju, Raisah Abdul Hadi, Abdul Rahman Izaini Ghani, Fauziah Mohamad Idris, Mirjana Maletic-Savatic, Jafri Malin Abdullah, and Hasnan Jaafar Copyright © 2014 Soumya Pati et al. All rights reserved. Altered Regional Homogeneity in Rolandic Epilepsy: A Resting-State fMRI Study Thu, 28 Aug 2014 00:00:00 +0000 Children with rolandic epilepsy (RE) are often associated with cognitive deficits and behavioral problems. Findings from neurophysiological and neuroimaging studies in RE have now demonstrated dysfunction not only in rolandic focus, but also in distant neuronal circuits. Little is known, however, about whether there is distributed abnormal spontaneous brain activity in RE. Using resting-state functional magnetic resonance imaging (RS-fMRI), the present study aimed to determine whether children with RE show abnormal local synchronization during resting state and, if so, whether these changes could be associated with the behavioral/clinical characteristics of RE. Regional homogeneity (ReHo) in children with RE and healthy children was computed on resting-state functional MRI data. In comparison with healthy children, children with RE showed increased ReHo in the central, premotor, and prefrontal regions, while they showed decreased ReHo in bilateral orbitofrontal cortex and temporal pole. In addition, the ReHo value in the left orbitofrontal cortex negatively was corrected with performance intelligence quotient in the children with RE. The aberrant local synchronization, not strictly related to primary site of the typical rolandic focus, indicates the neuropathophysiological mechanism of RE. The study findings may shed new light on the understanding of neural correlation of neuropsychological deficiencies in the children with RE. Ye-Lei Tang, Gong-Jun Ji, Yang Yu, Jue Wang, Zhong-Jin Wang, Yu-Feng Zang, Wei Liao, and Mei-Ping Ding Copyright © 2014 Ye-Lei Tang et al. All rights reserved. LRRK2 G2385R and R1628P Mutations Are Associated with an Increased Risk of Parkinson’s Disease in the Malaysian Population Thu, 28 Aug 2014 00:00:00 +0000 The LRRK2 gene has been associated with both familial and sporadic forms of Parkinson’s disease (PD). The G2019S variant is commonly found in North African Arab and Caucasian PD patients, but this locus is monomorphic in Asians. The G2385R and R1628P variants are associated with a higher risk of developing PD in certain Asian populations but have not been studied in the Malaysian population. Therefore, we screened the G2385R and R1628P variants in 1,202 Malaysian subjects consisting of 695 cases and 507 controls. The G2385R and R1628P variants were associated with a 2.2-fold () and 1.2-fold () increased risk of PD, respectively. Our data concur with other reported findings in Chinese, Taiwanese, Singaporean, and Korean studies. Aroma Agape Gopalai, Shen-Yang Lim, Jing Yi Chua, Shelisa Tey, Thien Thien Lim, Norlinah Mohamed Ibrahim, Ai Huey Tan, Gaik Bee Eow, Zariah Abdul Aziz, Santhi Datuk Puvanarajah, Shanthi Viswanathan, Irene Looi, Soo Kun Lim, Li Ping Tan, Yip Boon Chong, Chong Tin Tan, Yi Zhao, E. K. Tan, and Azlina Ahmad-Annuar Copyright © 2014 Aroma Agape Gopalai et al. All rights reserved. Lentivirus Mediated siRNA against GluN2B Subunit of NMDA Receptor Reduces Nociception in a Rat Model of Neuropathic Pain Thu, 28 Aug 2014 00:00:00 +0000 Although neuropathic pain (NP) is still not fully understood by scientists and clinicians alike, studies suggest that N-methyl-D-aspartate (NMDA) receptors play an important role in the induction and maintenance of NP. A promising treatment for NP is through the downregulation of NMDA subunit GluN2B by RNA interference; however, naked siRNA (small interference RNA) is not effective in long-term treatments. In order to concoct a viable prolonged treatment for NP, Lv-siGluN2B (lentivirus carrying siRNA targeting GluN2B subunit) was prepared and the antinociception effects were observed in chronic constriction injury (CCI) rats in the present study. Results showed that Lv-siGluN2B was transduced into spinal cord cells after intrathecal injections and effectively reduced the nociception induced by sciatic nerve ligation while inhibiting the mRNA and protein expression of GluN2B. This antinociception effect lasted approximately 7 weeks. These findings suggest that GluN2B subunit could be a target for NP treatment and Lv-siGluN2B represents a new potential option for long-term treatment of NP. Feixiang Wu, Ruirui Pan, Jiaying Chen, Megumi Sugita, Caiyang Chen, Yong Tao, Weifeng Yu, and Yuming Sun Copyright © 2014 Feixiang Wu et al. All rights reserved. Clinical Metabolomics and Nutrition: The New Frontier in Neonatology and Pediatrics Wed, 27 Aug 2014 08:47:36 +0000 In the pediatric clinic, nutritional research is focusing more and more on preventing the development of long-term diseases as well as supporting the repair processes important in the therapy of already fully developed diseases. Most children who are hospitalized or affected by chronic diseases could benefit from specific and careful attention to nutrition. Indeed, the state of nutrition modulates all body functions, including the different metabolic processes which, all together, have a profound effect on the development of the health and future of all individuals. Inappropriate food, even in the first periods of life, can accelerate the development of chronic metabolic diseases, especially in the pediatric age. To gain further insights into metabolic cycles and how they are connected with diet and health, nutrition and metabolomics interact to develop and apply modern technologies for metabolic assessment. In particular, nutritionists are evaluating the metabolomic approach to establish the single nutritional phenotypes, that is, the way in which diet interacts with individuals’ metabolisms. This strategy offers the possibility of providing a complete definition of the individual’s nutritional and health status, predict the risk of disease, and create metabolomic databases supporting the development of “personalized nutrition,” in which diet is attuned to the nutritional needs of individual patients. Angelica Dessì, Flaminia Cesare Marincola, Alice Masili, Diego Gazzolo, and Vassilios Fanos Copyright © 2014 Angelica Dessì et al. All rights reserved. Derailed Intraneuronal Signalling Drives Pathogenesis in Sporadic and Familial Alzheimer’s Disease Wed, 27 Aug 2014 00:00:00 +0000 Although a wide variety of genetic and nongenetic Alzheimer’s disease (AD) risk factors have been identified, their role in onset and/or progression of neuronal degeneration remains elusive. Systematic analysis of AD risk factors revealed that perturbations of intraneuronal signalling pathways comprise a common mechanistic denominator in both familial and sporadic AD and that such alterations lead to increases in Aβ oligomers (Aβo) formation and phosphorylation of TAU. Conversely, Aβo and TAU impact intracellular signalling directly. This feature entails binding of Aβo to membrane receptors, whereas TAU functionally interacts with downstream transducers. Accordingly, we postulate a positive feedback mechanism in which AD risk factors or genes trigger perturbations of intraneuronal signalling leading to enhanced Aβo formation and TAU phosphorylation which in turn further derange signalling. Ultimately intraneuronal signalling becomes deregulated to the extent that neuronal function and survival cannot be sustained, whereas the resulting elevated levels of amyloidogenic Aβo and phosphorylated TAU species self-polymerizes into the AD plaques and tangles, respectively. Tom Van Dooren, Katrien Princen, Koen De Witte, and Gerard Griffioen Copyright © 2014 Tom Van Dooren et al. All rights reserved. Gliomas Tue, 26 Aug 2014 13:10:34 +0000 Giuseppe Lombardi, Alessandro Della Puppa, Anna Luisa Di Stefano, Andrea Pace, Roberta Rudà, Emeline Tabouret, and Vittorina Zagonel Copyright © 2014 Giuseppe Lombardi et al. All rights reserved. Mutations in the ATP13A2 Gene and Parkinsonism: A Preliminary Review Thu, 14 Aug 2014 00:00:00 +0000 Parkinson’s disease (PD) is a major neurodegenerative disorder for which the etiology and pathogenesis remain as elusive as for Alzheimer's disease. PD appears to be caused by genetic and environmental factors, and pedigree and cohort studies have identified numerous susceptibility genes and loci related to PD. Autosomal recessive mutations in the genes Parkin, Pink1, DJ-1, ATP13A2, PLA2G6, and FBXO7 have been linked to PD susceptibility. Such mutations in ATP13A2, also named PARK9, were first identified in 2006 in a Chilean family and are associated with a juvenile-onset, levodopa-responsive type of Parkinsonism called Kufor-Rakeb syndrome (KRS). KRS involves pyramidal degeneration, supranuclear palsy, and cognitive impairment. Here we review current knowledge about the ATP13A2 gene, clinical characteristics of patients with PD-associated ATP13A2 mutations, and models of how the ATP13A2 protein may help prevent neurodegeneration by inhibiting α-synuclein aggregation and supporting normal lysosomal and mitochondrial function. We also discuss another ATP13A2 mutation that is associated with the family of neurodegenerative disorders called neuronal ceroid lipofuscinoses (NCLs), and we propose a single pathway whereby ATP13A2 mutations may contribute to NCLs and Parkinsonism. Finally, we highlight how studies of mutations in this gene may provide new insights into PD pathogenesis and identify potential therapeutic targets. Xinglong Yang and Yanming Xu Copyright © 2014 Xinglong Yang and Yanming Xu. All rights reserved. Adult Stem Cell as New Advanced Therapy for Experimental Neuropathic Pain Treatment Wed, 13 Aug 2014 08:05:23 +0000 Neuropathic pain (NP) is a highly invalidating disease resulting as consequence of a lesion or disease affecting the somatosensory system. All the pharmacological treatments today in use give a long lasting pain relief only in a limited percentage of patients before pain reappears making NP an incurable disease. New approaches are therefore needed and research is testing stem cell usage. Several papers have been written on experimental neuropathic pain treatment using stem cells of different origin and species to treat experimental NP. The original idea was based on the capacity of stem cell to offer a totipotent cellular source for replacing injured neural cells and for delivering trophic factors to lesion site; soon the researchers agreed that the capacity of stem cells to contrast NP was not dependent upon their regenerative effect but was mostly linked to a bidirectional interaction between the stem cell and damaged microenvironment resident cells. In this paper we review the preclinical studies produced in the last years assessing the effects induced by several stem cells in different models of neuropathic pain. The overall positive results obtained on pain remission by using stem cells that are safe, of easy isolation, and which may allow an autologous transplant in patients may be encouraging for moving from bench to bedside, although there are several issues that still need to be solved. Silvia Franchi, Mara Castelli, Giada Amodeo, Stefania Niada, Daniela Ferrari, Angelo Vescovi, Anna Teresa Brini, Alberto Emilio Panerai, and Paola Sacerdote Copyright © 2014 Silvia Franchi et al. All rights reserved. The Mouse Median Nerve Experimental Model in Regenerative Research Mon, 11 Aug 2014 07:12:17 +0000 Sciatic nerve crush injury in rat animal model is one of the most common experimental models used in regenerative research. However, the availability of transgenic mouse for nerve regeneration studies is constantly increasing and, therefore, the shift from rat model to mouse model is, in some cases, necessary. Moreover, since most of the human nerve lesions occur in the upper limb, it is also advantageous to shift from sciatic nerve to median nerve. In this study we described an experimental model which involves lesions of the median nerve in the mouse. Data showed that the finger flexor muscle contraction strength, assessed to evaluate the motor function recovery, and reached values not different from the control already 20 days after injury. The degree of nerve regeneration evaluated with stereological methods in light microscopy showed that, 25 days after injury, the number of regenerated myelinated fibers was comparable to the control, but they were smaller with a thinner myelin thickness. Stereological analysis made in electron microscopy confirmed these results, although the total number of fibers quantified was significantly higher compared to light microscopy analysis, due to the very small size of some fibers that can be detected only in electron microscopy. Sara Buskbjerg Jager, Giulia Ronchi, Christian Bjerggaard Vaegter, and Stefano Geuna Copyright © 2014 Sara Buskbjerg Jager et al. All rights reserved. Parkia biglobosa Improves Mitochondrial Functioning and Protects against Neurotoxic Agents in Rat Brain Hippocampal Slices Sun, 10 Aug 2014 08:48:46 +0000 Objective. Methanolic leaf extracts of Parkia biglobosa, PBE, and one of its major polyphenolic constituents, catechin, were investigated for their protective effects against neurotoxicity induced by different agents on rat brain hippocampal slices and isolated mitochondria. Methods. Hippocampal slices were preincubated with PBE (25, 50, 100, or 200 µg/mL) or catechin (1, 5, or 10 µg/mL) for 30 min followed by further incubation with 300 µM H2O2, 300 µM SNP, or 200 µM PbCl2 for 1 h. Effects of PBE and catechin on SNP- or CaCl2-induced brain mitochondrial ROS formation and mitochondrial membrane potential () were also determined. Results. PBE and catechin decreased basal ROS generation in slices and blunted the prooxidant effects of neurotoxicants on membrane lipid peroxidation and nonprotein thiol contents. PBE rescued hippocampal cellular viability from SNP damage and caused a significant boost in hippocampus Na+, K+-ATPase activity but with no effect on the acetylcholinesterase activity. Both PBE and catechin also mitigated SNP- or CaCl2-dependent mitochondrial ROS generation. Measurement by safranine fluorescence however showed that the mild depolarization of the by PBE was independent of catechin. Conclusion. The results suggest that the neuroprotective effect of PBE is dependent on its constituent antioxidants and mild mitochondrial depolarization propensity. Kayode Komolafe, Tolulope M. Olaleye, Rodrigo L. Seeger, Fabiano B. Carvalho, Aline A. Boligon, Margareth L. Athayde, Claudia V. Klimaczewski, Akintunde A. Akindahunsi, and Joao B. T. Rocha Copyright © 2014 Kayode Komolafe et al. All rights reserved. Characterization of Glial Cell Models and In Vitro Manipulation of the Neuregulin1/ErbB System Thu, 07 Aug 2014 10:45:42 +0000 The neuregulin1/ErbB system plays an important role in Schwann cell behavior both in normal and pathological conditions. Upon investigation of the expression of the neuregulin1/ErbB system in vitro, we explored the possibility to manipulate the system in order to increase the migration of Schwann cells, that play a fundamental role in the peripheral nerve regeneration. Comparison of primary cells and stable cell lines shows that both primary olfactory bulb ensheathing cells and a corresponding cell line express ErbB1-ErbB2 and neuregulin1, and that both primary Schwann cells and a corresponding cell line express ErbB2-ErbB3, while only primary Schwann cells express neuregulin1. To interfere with the neuregulin1/ErbB system, the soluble extracellular domain of the neuregulin1 receptor ErbB4 (ecto-ErbB4) was expressed in vitro in the neuregulin1 expressing cell line, and an unexpected increase in cell motility was observed. In vitro experiments suggest that the back signaling mediated by the transmembrane neuregulin1 plays a role in the migratory activity induced by ecto-ErbB4. These results indicate that ecto-ErbB4 could be used in vivo as a tool to manipulate the neuregulin1/ErbB system. Davide Pascal, Alessia Giovannelli, Sara Gnavi, Stefan Adriaan Hoyng, Fred de Winter, Michela Morano, Federica Fregnan, Paola Dell'Albani, Damiano Zaccheo, Isabelle Perroteau, Rosalia Pellitteri, and Giovanna Gambarotta Copyright © 2014 Davide Pascal et al. All rights reserved. Cyclic AMP Signaling: A Molecular Determinant of Peripheral Nerve Regeneration Thu, 07 Aug 2014 09:09:28 +0000 Disruption of axonal integrity during injury to the peripheral nerve system (PNS) sets into motion a cascade of responses that includes inflammation, Schwann cell mobilization, and the degeneration of the nerve fibers distal to the injury site. Yet, the injured PNS differentiates itself from the injured central nervous system (CNS) in its remarkable capacity for self-recovery, which, depending upon the length and type of nerve injury, involves a series of molecular events in both the injured neuron and associated Schwann cells that leads to axon regeneration, remyelination repair, and functional restitution. Herein we discuss the essential function of the second messenger, cyclic adenosine monophosphate (cyclic AMP), in the PNS repair process, highlighting the important role the conditioning lesion paradigm has played in understanding the mechanism(s) by which cyclic AMP exerts its proregenerative action. Furthermore, we review the studies that have therapeutically targeted cyclic AMP to enhance endogenous nerve repair. Eric P. Knott, Mazen Assi, and Damien D. Pearse Copyright © 2014 Eric P. Knott et al. All rights reserved. Wavelet Analysis Increases Sensitivity and Specificity of Spirography for Ambulatory Tremor Discrimination Wed, 06 Aug 2014 07:57:50 +0000 The most frequently seen types of tremor are essential (ET) and parkinsonian tremor (PT) and in some patients clinical characteristics of these tremor types overlap. It is vital to distinguish between these two types of tremor in order to reach the right diagnosis and select the appropriate treatment. One of the widely used methods for tremor detection and discrimination, appropriate for a quick ambulatory assessment of the patient’s tremor, is spirography. With spirography, the tremor can be observed through several parameters, for example, tremor spectrum and spiral image, which give useful information for its identification. Standard spirography parameters of ET and PT can overlap; therefore, these parameters are often not enough for identification of the observed tremor. To increase the specificity and sensitivity of spirography for PT, ET and normal, tremor free controls, we used the wavelet analysis with Morlet wavelet transform. To facilitate analysis, comparison, storage, and retrieval of spirography tremor records we also developed an integrated computer assisted spirography system that increases the convenience of outpatient tremor identification and follow-up. We conclude that wavelet analysis of spirography records increases the sensitivity and specificity of the method, thus, facilitating the distinction between ET and PT. Veronika Kragelj, Dejan Georgiev, Zvezdan Pirtošek, and Samo Ribarič Copyright © 2014 Veronika Kragelj et al. All rights reserved. Transgenic Rat Model of Huntington’s Disease: A Histopathological Study and Correlations with Neurodegenerative Process in the Brain of HD Patients Sun, 03 Aug 2014 08:02:44 +0000 Rats transgenic for Huntington’s disease (tgHD51 CAG rats), surviving up to two years, represent an animal model of HD similar to the late-onset form of human disease. This enables us to follow histopathological changes in course of neurodegenerative process (NDP) within the striatum and compare them with postmortem samples of human HD brains. A basic difference between HD pathology in human and tgHD51 rats is in the rate of NDP progression that originates primarily from slow neuronal degeneration consequently resulting in lesser extent of concomitant reactive gliosis in the brain of tgHD51 rats. Although larger amount of striatal neurons displays only gradual decrease in their size, their number is significantly reduced in the oldest tgHD51 rats. Our quantitative analysis proved that the end of the first year represents the turn in the development of morphological changes related to the progression of NDP in tgHD51 rats. Our data also support the view that all types of CNS glial cells play an important, irreplaceable role in NDP. To the best of our knowledge, our findings are the first to document that tgHD51 CAG rats can be used as a valid animal model for detailed histopathological studies related to HD in human. Yvona Mazurová, Miroslava Anderova, Ivana Němečková, and Aleš Bezrouk Copyright © 2014 Yvona Mazurová et al. All rights reserved. Innervation of a Prefabricated Flap: A New Experimental Model Thu, 24 Jul 2014 09:27:39 +0000 Introduction. Flap innervation by neoaxonogenesis is a promising field of investigation. The authors evaluated the possibility of innervating an acellular collagen scaffold as component of a potential prefabricated flap. Materials and Methods. Collagen matrix sheets were implanted around the femoral bundle of a murine model to produce two flaps on proximal and distal nerve stumps based on a flow-through model. After thirty days, nerve regeneration and integration into the collagen matrix were evaluated. The specimens were microscopically analyzed to study Schwann cell colonization and axonal integration with the matrix. Axonal count and density were assessed and statistically evaluated. Results. Qualitative structural and ultrastructural evaluation indicated integration, with axonal fibers merged within the collagen matrix, along with a newly formed vascular network on the proximal flap. Wallerian degeneration occurred inside the distal chamber. Axonal count and density did not show statistically significant differences between the nerve inside the proximal flap and the control side. Conclusions. Innervation of an acellular matrix can be obtained by direct nerve stump implantation. The flow-through system was relatively easy to build and reliable to provide adequate blood supply. The collagen scaffold may be a promising support or further studies of preinnervated microsurgical flaps. Marco Romeo, Giuseppe Cuccia, Shan Shan Qiu, Stefania Raimondo, Stefano Geuna, and Bernardo Hontanilla Copyright © 2014 Marco Romeo et al. All rights reserved. The Parameters of Transcutaneous Electrical Nerve Stimulation Are Critical to Its Regenerative Effects When Applied Just after a Sciatic Crush Lesion in Mice Thu, 24 Jul 2014 07:56:08 +0000 We investigated the effect of two frequencies of transcutaneous electrical nerve stimulation (TENS) applied immediately after lesion on peripheral nerve regeneration after a mouse sciatic crush injury. The animals were anesthetized and subjected to crushing of the right sciatic nerve and then separated into three groups: nontreated, Low-TENS (4 Hz), and High-TENS (100 Hz). The animals of Low- and High-TENS groups were stimulated for 2 h immediately after the surgical procedure, while the nontreated group was only positioned for the same period. After five weeks the animals were euthanized, and the nerves dissected bilaterally for histological and histomorphometric analysis. Histological assessment by light and electron microscopy showed that High-TENS and nontreated nerves had a similar profile, with extensive signs of degeneration. Conversely, Low-TENS led to increased regeneration, displaying histological aspects similar to control nerves. High-TENS also led to decreased density of fibers in the range of 6–12 μm diameter and decreased fiber diameter and myelin area in the range of 0–2 μm diameter. These findings suggest that High-TENS applied just after a peripheral nerve crush may be deleterious for regeneration, whereas Low-TENS may increase nerve regeneration capacity. Diana Cavalcante Miranda de Assis, Êmyle Martins Lima, Bruno Teixeira Goes, João Zugaib Cavalcanti, Alaí Barbosa Paixão, Marcos André Vannier-Santos, Ana Maria Blanco Martinez, and Abrahão Fontes Baptista Copyright © 2014 Diana Cavalcante Miranda de Assis et al. All rights reserved. Impact of Statins on Cognitive Deficits in Adult Male Rodents after Traumatic Brain Injury: A Systematic Review Wed, 23 Jul 2014 11:03:25 +0000 The efficacy of statin treatment on cognitive decline is controversial, and the effect of statins on cognitive deficits in individuals with traumatic brain injury (TBI) has yet to be investigated. Therefore, we systematically reviewed the effect of statins on cognitive deficits in adult male rodents after TBI. After identifying eligible studies by searching four electronic databases on February 28, 2014, we assessed study quality, evaluated the efficacy of statin treatment, and performed stratified metaregression and metaregression to assess the influence of study design on statin efficacy. Eleven studies fulfilled our inclusion criteria from a total of 183 publications. The overall methodological quality of these studies was poor. Meta-analysis showed that statins exert statistically significant positive effects on cognitive performance after TBI. Stratified analysis showed that atorvastatin has the greatest effect on acquisition memory, simvastatin has the greatest effect on retention memory, and statin effects on acquisition memory are higher in closed head injury models. Metaregression analysis further showed that that animal species, study quality, and anesthetic agent impact statin effects on retention memory. We conclude that statins might reduce cognitive deficits after TBI. However, additional well-designed and well-reported animal studies are needed to inform further clinical study. Weijun Peng, Jingjing Yang, Bo Yang, Lexing Wang, Xin-gui Xiong, and Qinghua Liang Copyright © 2014 Weijun Peng et al. All rights reserved. The Emerging Use of In Vivo Optical Imaging in the Study of Neurodegenerative Diseases Wed, 23 Jul 2014 09:01:59 +0000 The detection and subsequent quantification of photons emitted from living tissues, using highly sensitive charged-couple device (CCD) cameras, have enabled investigators to noninvasively examine the intricate dynamics of molecular reactions in wide assortment of experimental animals under basal and pathophysiological conditions. Nevertheless, extrapolation of this in vivo optical imaging technology to the study of the mammalian brain and related neurodegenerative conditions is still in its infancy. In this review, we introduce the reader to the emerging use of in vivo optical imaging in the study of neurodegenerative diseases. We highlight the current instrumentation that is available and reporter molecules (fluorescent and bioluminescent) that are commonly used. Moreover, we examine how in vivo optical imaging using transgenic reporter mice has provided new insights into Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Prion disease, and neuronal damage arising from excitotoxicity and inflammation. Furthermore, we also touch upon studies that have utilized these technologies for the development of therapeutic strategies for neurodegenerative conditions that afflict humans. Aileen P. Patterson, Stephanie A. Booth, and Reuben Saba Copyright © 2014 Aileen P. Patterson et al. All rights reserved. Apocynin, a Low Molecular Oral Treatment for Neurodegenerative Disease Tue, 22 Jul 2014 00:00:00 +0000 Accumulating evidence suggests that inflammatory mediators secreted by activated resident or infiltrated innate immune cells have a significant impact on the pathogenesis of neurodegenerative diseases. This may imply that patients affected by a neurodegenerative disease may benefit from treatment with selective inhibitors of innate immune activity. Here we review the therapeutic potential of apocynin, an essentially nontoxic phenolic compound isolated from the medicinal plant Jatropha multifida. Apocynin is a selective inhibitor of the phagocyte NADPH oxidase Nox2 that can be applied orally and is remarkably effective at low dose. Bert A. ‘t Hart, Sjef Copray, and Ingrid Philippens Copyright © 2014 Bert A. ‘t Hart et al. All rights reserved. A Review of Bioactive Release from Nerve Conduits as a Neurotherapeutic Strategy for Neuronal Growth in Peripheral Nerve Injury Mon, 21 Jul 2014 09:38:46 +0000 Peripheral nerve regeneration strategies employ the use of polymeric engineered nerve conduits encompassed with components of a delivery system. This allows for the controlled and sustained release of neurotrophic growth factors for the enhancement of the innate regenerative capacity of the injured nerves. This review article focuses on the delivery of neurotrophic factors (NTFs) and the importance of the parameters that control release kinetics in the delivery of optimal quantities of NTFs for improved therapeutic effect and prevention of dose dumping. Studies utilizing various controlled-release strategies, in attempt to obtain ideal release kinetics, have been reviewed in this paper. Release strategies discussed include affinity-based models, crosslinking techniques, and layer-by-layer technologies. Currently available synthetic hollow nerve conduits, an alternative to the nerve autografts, have proven to be successful in the bridging and regeneration of primarily the short transected nerve gaps in several patient cases. However, current research emphasizes on the development of more advanced nerve conduits able to simulate the effectiveness of the autograft which includes, in particular, the ability to deliver growth factors. Poornima Ramburrun, Pradeep Kumar, Yahya E. Choonara, Divya Bijukumar, Lisa C. du Toit, and Viness Pillay Copyright © 2014 Poornima Ramburrun et al. All rights reserved. Does Pulsed Magnetic Field Therapy Influence Nerve Regeneration in the Median Nerve Model of the Rat? Mon, 21 Jul 2014 06:59:21 +0000 The aim of this study was to evaluate the impact of pulsed magnetic field therapy on peripheral nerve regeneration after median nerve injury and primary coaptation in the rat. Both median nerves were surgically exposed and denervated in 24 female Wistar rats. A microsurgical coaptation was performed on the right side, whereas on the left side a spontaneous healing was prevented. The study group underwent a daily pulsed magnetic field therapy; the other group served as a control group. The grasping force was recorded 2 weeks after the surgical intervention for a period of 12 weeks. The right median nerve was excised and histologically examined. The histomorphometric data and the functional assessments were analyzed by t-test statistics and one-way ANOVA. One-way ANOVA indicated a statistically significant influence of group affiliation and grasping force . Grasping strength was higher on a significant level in the experimental group compared to the control group permanently from the 9th week to the end of the study. T-test statistics revealed a significantly higher weight of the flexor digitorum sublimis muscle in the experimental group. The histological evaluation did not reveal any statistically significant differences concerning the histomorphometric parameters. Our results suggest that the pulsed magnetic field therapy has a positive influence on the functional aspects of neural regeneration. More studies are needed to precisely evaluate and optimize the intensity and duration of the application. Benedicta E. Beck-Broichsitter, Androniki Lamia, Stefano Geuna, Federica Fregnan, Ralf Smeets, Stephan T. Becker, and Nektarios Sinis Copyright © 2014 Benedicta E. Beck-Broichsitter et al. All rights reserved. Clinical Applications of End-to-Side Neurorrhaphy: An Update Sun, 20 Jul 2014 10:20:41 +0000 End-to-side neurorrhaphy constitutes an interesting option to regain nerve function after damage in selected cases, in which conventional techniques are not feasible. In the last twenty years, many experimental and clinical studies have been conducted in order to understand the biological mechanisms and to test the effectiveness of this technique, with contrasting results. In this updated review, we consider the state of the art about end-to-side coaptation, focusing on all the current clinical applications, such as sensory and mixed nerve repair, treatment of facial palsy, and brachial plexus injuries and painful neuromas management. Pierluigi Tos, Giulia Colzani, Davide Ciclamini, Paolo Titolo, Pierfrancesco Pugliese, and Stefano Artiaco Copyright © 2014 Pierluigi Tos et al. All rights reserved. Potential Therapeutic Strategies for Alzheimer’s Disease Targeting or Beyond β-Amyloid: Insights from Clinical Trials Thu, 17 Jul 2014 11:54:59 +0000 Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with two hallmarks: β-amyloid plagues and neurofibrillary tangles. It is one of the most alarming illnesses to elderly people. No effective drugs and therapies have been developed, while mechanism-based explorations of therapeutic approaches have been intensively investigated. Outcomes of clinical trials suggested several pitfalls in the choice of biomarkers, development of drug candidates, and interaction of drug-targeted molecules; however, they also aroused concerns on the potential deficiency in our understanding of pathogenesis of AD, and ultimately stimulated the advent of novel drug targets tests. The anticipated increase of AD patients in next few decades makes development of better therapy an urgent issue. Here we attempt to summarize and compare putative therapeutic strategies that have completed clinical trials or are currently being tested from various perspectives to provide insights for treatments of Alzheimer’s disease. Qiutian Jia, Yulin Deng, and Hong Qing Copyright © 2014 Qiutian Jia et al. All rights reserved. Alternative Splicing Generates Different Parkin Protein Isoforms: Evidences in Human, Rat, and Mouse Brain Wed, 16 Jul 2014 06:57:07 +0000 Parkinson protein 2, E3 ubiquitin protein ligase (PARK2) gene mutations are the most frequent causes of autosomal recessive early onset Parkinson’s disease and juvenile Parkinson disease. Parkin deficiency has also been linked to other human pathologies, for example, sporadic Parkinson disease, Alzheimer disease, autism, and cancer. PARK2 primary transcript undergoes an extensive alternative splicing, which enhances transcriptomic diversification. To date several PARK2 splice variants have been identified; however, the expression and distribution of parkin isoforms have not been deeply investigated yet. Here, the currently known PARK2 gene transcripts and relative predicted encoded proteins in human, rat, and mouse are reviewed. By analyzing the literature, we highlight the existing data showing the presence of multiple parkin isoforms in the brain. Their expression emerges from conflicting results regarding the electrophoretic mobility of the protein, but it is also assumed from discrepant observations on the cellular and tissue distribution of parkin. Although the characterization of each predicted isoforms is complex, since they often diverge only for few amino acids, analysis of their expression patterns in the brain might account for the different pathogenetic effects linked to PARK2 gene mutations. Soraya Scuderi, Valentina La Cognata, Filippo Drago, Sebastiano Cavallaro, and Velia D'Agata Copyright © 2014 Soraya Scuderi et al. All rights reserved. The Role of Neurotrophic Factors Conjugated to Iron Oxide Nanoparticles in Peripheral Nerve Regeneration: In Vitro Studies Wed, 16 Jul 2014 00:00:00 +0000 Local delivery of neurotrophic factors is a pillar of neural repair strategies in the peripheral nervous system. The main disadvantage of the free growth factors is their short half-life of few minutes. In order to prolong their activity, we have conjugated to iron oxide nanoparticles three neurotrophic factors: nerve growth factor (βNGF), glial cell-derived neurotrophic factor (GDNF), and basic fibroblast growth factor (FGF-2). Comparative stability studies of free versus conjugated factors revealed that the conjugated neurotrophic factors were significantly more stable in tissue cultures and in medium at 37°C. The biological effects of free versus conjugated neurotrophic factors were examined on organotypic dorsal root ganglion (DRG) cultures performed in NVR-Gel, composed mainly of hyaluronic acid and laminin. Results revealed that the conjugated neurotrophic factors enhanced early nerve fiber sprouting compared to the corresponding free factors. The most meaningful result was that conjugated-GDNF, accelerated the onset and progression of myelin significantly earlier than the free GDNF and the other free and conjugated factors. This is probably due to the beneficial and long-acting effect that the stabilized conjugated-GDNF had on neurons and Schwann cells. These conclusive results make NVR-Gel enriched with conjugated-GDNF, a desirable scaffold for the reconstruction of severed peripheral nerve. Ofra Ziv-Polat, Abraham Shahar, Itay Levy, Hadas Skaat, Sara Neuman, Federica Fregnan, Stefano Geuna, Claudia Grothe, Kirsten Haastert-Talini, and Shlomo Margel Copyright © 2014 Ofra Ziv-Polat et al. All rights reserved. Nerve Regenerative Effects of GABA-B Ligands in a Model of Neuropathic Pain Tue, 15 Jul 2014 09:02:02 +0000 Neuropathic pain arises as a direct consequence of a lesion or disease affecting the peripheral somatosensory system. It may be associated with allodynia and increased pain sensitivity. Few studies correlated neuropathic pain with nerve morphology and myelin proteins expression. Our aim was to test if neuropathic pain is related to nerve degeneration, speculating whether the modulation of peripheral GABA-B receptors may promote nerve regeneration and decrease neuropathic pain. We used the partial sciatic ligation- (PSL-) induced neuropathic model. The biochemical, morphological, and behavioural outcomes of sciatic nerve were analysed following GABA-B ligands treatments. Simultaneous 7-days coadministration of baclofen (10 mg/kg) and CGP56433 (3 mg/kg) alters tactile hypersensitivity. Concomitantly, specific changes of peripheral nerve morphology, nerve structure, and myelin proteins (P0 and PMP22) expression were observed. Nerve macrophage recruitment decreased and step coordination was improved. The PSL-induced changes in nociception correlate with altered nerve morphology and myelin protein expression. Peripheral synergic effects, via GABA-B receptor activation, promote nerve regeneration and likely ameliorate neuropathic pain. Valerio Magnaghi, Luca Franco Castelnovo, Alessandro Faroni, Erica Cavalli, Lucia Caffino, Alessandra Colciago, Patrizia Procacci, and Giorgio Pajardi Copyright © 2014 Valerio Magnaghi et al. All rights reserved. Sensoric Protection after Median Nerve Injury: Babysitter-Procedure Prevents Muscular Atrophy and Improves Neuronal Recovery Tue, 15 Jul 2014 07:03:53 +0000 The babysitter-procedure might offer an alternative when nerve reconstruction is delayed in order to overcome muscular atrophy due to denervation. In this study we aimed to show that a sensomotoric babysitter-procedure after median nerve injury is capable of preserving irreversible muscular atrophy. The median nerve of 20 female Wistar rats was denervated. 10 animals received a sensory protection with the N. cutaneous brachii. After six weeks the median nerve was reconstructed by autologous nerve grafting from the contralateral median nerve in the babysitter and the control groups. Grasping tests measured functional recovery over 15 weeks. At the end of the observation period the weight of the flexor digitorum sublimis muscle was determined. The median nerve was excised for histological examinations. Muscle weight () was significantly superior in the babysitter group compared to the control group at the end of the study. The histological evaluation revealed a significantly higher diameter of axons (), nerve fiber (), and nerve surface () in the babysitter group. We conclude that sensory protection of a motor nerve is capable of preserving muscule weight and we may presume that metabolism of the sensory nerve was sufficient to keep the target muscle’s weight and vitality. Benedicta E. Beck-Broichsitter, Stephan T. Becker, Androniki Lamia, Federica Fregnan, Stefano Geuna, and Nektarios Sinis Copyright © 2014 Benedicta E. Beck-Broichsitter et al. All rights reserved. Reduction of Experimental Cerebral Malaria and Its Related Proinflammatory Responses by the Novel Liposome-Based β-Methasone Nanodrug Mon, 14 Jul 2014 00:00:00 +0000 Cerebral malaria (CM) is a severe complication of and a leading cause of death due to Plasmodium falciparum infection. CM is likely the result of interrelated events, including mechanical obstruction due to parasite sequestration in the microvasculature, and upregulation of Th1 immune responses. In parallel, blood-brain-barrier (BBB) breakdown and damage or death of microglia, astrocytes, and neurons occurs. We found that a novel formulation of a liposome-encapsulated glucocorticosteroid, β-methasone hemisuccinate (nSSL-BMS), prevents experimental cerebral malaria (ECM) in a murine model and creates a survival time-window, enabling administration of an antiplasmodial drug before severe anemia develops. nSSL-BMS treatment leads to lower levels of cerebral inflammation, expressed by altered levels of corresponding cytokines and chemokines. The results indicate the role of integrated immune responses in ECM induction and show that the new steroidal nanodrug nSSL-BMS reverses the balance between the Th1 and Th2 responses in malaria-infected mice so that the proinflammatory processes leading to ECM are prevented. Overall, because of the immunopathological nature of CM, combined immunomodulator/antiplasmodial treatment should be considered for prevention/treatment of human CM and long-term cognitive damage. Jintao Guo, Judith H. Waknine-Grinberg, Andrew J. Mitchell, Yechezkel Barenholz, and Jacob Golenser Copyright © 2014 Jintao Guo et al. All rights reserved. Improvement of Oxidative and Metabolic Parameters by Cellfood Administration in Patients Affected by Neurodegenerative Diseases on Chelation Treatment Thu, 10 Jul 2014 11:39:32 +0000 Objective. This prospective pilot study aimed at evaluating the effects of therapy with antioxidant compounds (Cellfood, and other antioxidants) on patients affected by neurodegenerative diseases (ND), who displayed toxic metal burden and were subjected to chelation treatment with the chelating agent calcium disodium ethylenediaminetetraacetic acid (CaNa2EDTA or EDTA). Methods. Two groups of subjects were studied: (a) 39 patients affected by ND and (b) 11 subjects unaffected by ND (controls). The following blood parameters were analyzed before and after three months’ treatment with chelation + Cellfood or chelation + other antioxidants: oxidative status (reactive oxygen species, ROS; total antioxidant capacity, TAC; oxidized LDL, oxLDL; glutathione), homocysteine, vitamin B12, and folate. Results. After 3-months’ chelation + Cellfood administration oxLDL decreased, ROS levels were significantly lower, and TAC and glutathione levels were significantly higher than after chelation + other antioxidants treatment, both in ND patients and in controls. Moreover, homocysteine metabolism had also improved in both groups. Conclusions. Chelation + Cellfood treatment was more efficient than chelation + other antioxidants improving oxidative status and homocysteine metabolism significantly in ND patients and controls. Although limited to a small number of cases, this study showed how helpful antioxidant treatment with Cellfood was in improving the subjects’ metabolic conditions. Alessandro Fulgenzi, Rachele De Giuseppe, Fabrizia Bamonti, and Maria Elena Ferrero Copyright © 2014 Alessandro Fulgenzi et al. All rights reserved. Advanced User Interfaces for Neurorehabilitation Thu, 10 Jul 2014 06:51:22 +0000 Alessandro De Mauro, Belinda Lange, and Andreas Dünser Copyright © 2014 Alessandro De Mauro et al. All rights reserved. Promoting Nerve Regeneration in a Neurotmesis Rat Model Using Poly(DL-lactide--caprolactone) Membranes and Mesenchymal Stem Cells from the Wharton’s Jelly: In Vitro and In Vivo Analysis Thu, 10 Jul 2014 00:00:00 +0000 In peripheral nerves MSCs can modulate Wallerian degeneration and the overall regenerative response by acting through paracrine mechanisms directly on regenerating axons or upon the nerve-supporting Schwann cells. In the present study, the effect of human MSCs from Wharton’s jelly (HMSCs), differentiated into neuroglial-like cells associated to poly (DL-lactide-ε-caprolactone) membrane, on nerve regeneration, was evaluated in the neurotmesis injury rat sciatic nerve model. Results in vitro showed successful differentiation of HMSCs into neuroglial-like cells, characterized by expression of specific neuroglial markers confirmed by immunocytochemistry and by RT-PCR and qPCR targeting specific genes expressed. In vivo testing evaluated during the healing period of 20 weeks, showed no evident positive effect of HMSCs or neuroglial-like cell enrichment at the sciatic nerve repair site on most of the functional and nerve morphometric predictors of nerve regeneration although the nociception function was almost normal. EPT on the other hand, recovered significantly better after HMSCs enriched membrane employment, to values of residual functional impairment compared to other treated groups. When the neurotmesis injury can be surgically reconstructed with an end-to-end suture or by grafting, the addition of a PLC membrane associated with HMSCs seems to bring significant advantage, especially concerning the motor function recovery. T. Pereira, A. Gärtner, I. Amorim, A. Almeida, A. R. Caseiro, Paulo A. S. Armada-da-Silva, Sandra Amado, Federica Fregnan, A. S. P. Varejão, J. D. Santos, P. J. Bartolo, S. Geuna, A. L. Luís, and A. C. Mauricio Copyright © 2014 T. Pereira et al. All rights reserved. Changes in Cortical Thickness in 6-Year-Old Children Open Their Mind to a Global Vision of the World Wed, 09 Jul 2014 00:00:00 +0000 Even if objectively presented with similar visual stimuli, children younger than 6 years of age exhibit a strong attraction to local visual information (e.g., the trees), whereas children older than 6 years of age, similar to adults, exhibit a visual bias toward global information (e.g., the forest). Here, we studied the cortical thickness changes that underlie this bias shift from local to global visual information. Two groups, matched for age, gender, and handedness, were formed from a total of 30 children who were 6 years old, and both groups performed a traditional global/local visual task. The first group presented a local visual bias, and the other group presented a global visual bias. The results indicated that, compared with the local visual bias group, children with a global visual bias exhibited (1) decreased cortical thickness in the bilateral occipital regions and (2) increased cortical thickness in the left frontoparietal regions. These findings constitute the first structural study that supports the view that both synaptic pruning (i.e., decreased cortical thickness) and expansion mechanisms (i.e., increased cortical thickness) cooccur to allow healthy children to develop a global perception of the visual world. Nicolas Poirel, Elise Leroux, Arlette Pineau, Olivier Houdé, and Grégory Simon Copyright © 2014 Nicolas Poirel et al. All rights reserved. Gambling Disorder during Dopamine Replacement Treatment in Parkinson’s Disease: A Comprehensive Review Tue, 08 Jul 2014 12:00:04 +0000 Gambling Disorder (GD) is characterized by “the failure to resist gambling impulses despite severe personal, family or occupational consequences”. In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), GD replaces the DSM-IV diagnosis of Pathological Gambling (PG). GD estimated prevalence ranges between 0.4% and 3.4% within the adult population and it seems to be more common in patients with Parkinson’s disease (PD). In this population, GD recently has become more widely recognized as a possible complication of dopamine agonist (DA) therapy. This association has aroused great interest for the dramatic impact GD has on patients’ quality of life. Management of PG in patients with PD could be demanding. It is based on patient and caregiver education, modification of dopamine replacement therapy, and in some cases psychoactive drug administration. In this review article, the authors provide an overview of GD pathogenesis during DA therapy as well as a summary of available treatment options. Domenico Pirritano, Massimiliano Plastino, Domenico Bosco, Luca Gallelli, Antonio Siniscalchi, and Giovambattista De Sarro Copyright © 2014 Domenico Pirritano et al. All rights reserved. Upper Limb Posture Estimation in Robotic and Virtual Reality-Based Rehabilitation Tue, 08 Jul 2014 08:18:13 +0000 New motor rehabilitation therapies include virtual reality (VR) and robotic technologies. In limb rehabilitation, limb posture is required to (1) provide a limb realistic representation in VR games and (2) assess the patient improvement. When exoskeleton devices are used in the therapy, the measurements of their joint angles cannot be directly used to represent the posture of the patient limb, since the human and exoskeleton kinematic models differ. In response to this shortcoming, we propose a method to estimate the posture of the human limb attached to the exoskeleton. We use the exoskeleton joint angles measurements and the constraints of the exoskeleton on the limb to estimate the human limb joints angles. This paper presents (a) the mathematical formulation and solution to the problem, (b) the implementation of the proposed solution on a commercial exoskeleton system for the upper limb rehabilitation, (c) its integration into a rehabilitation VR game platform, and (d) the quantitative assessment of the method during elbow and wrist analytic training. Results show that this method properly estimates the limb posture to (i) animate avatars that represent the patient in VR games and (ii) obtain kinematic data for the patient assessment during elbow and wrist analytic rehabilitation. Camilo Cortés, Aitor Ardanza, F. Molina-Rueda, A. Cuesta-Gómez, Luis Unzueta, Gorka Epelde, Oscar E. Ruiz, Alessandro De Mauro, and Julian Florez Copyright © 2014 Camilo Cortés et al. All rights reserved. Recovery of Peripheral Nerve with Massive Loss Defect by Tissue Engineered Guiding Regenerative Gel Thu, 03 Jul 2014 07:46:57 +0000 Objective. Guiding Regeneration Gel (GRG) was developed in response to the clinical need of improving treatment for peripheral nerve injuries and helping patients regenerate massive regional losses in peripheral nerves. The efficacy of GRG based on tissue engineering technology for the treatment of complete peripheral nerve injury with significant loss defect was investigated. Background. Many severe peripheral nerve injuries can only be treated through surgical reconstructive procedures. Such procedures are challenging, since functional recovery is slow and can be unsatisfactory. One of the most promising solutions already in clinical practice is synthetic nerve conduits connecting the ends of damaged nerve supporting nerve regeneration. However, this solution still does not enable recovery of massive nerve loss defect. The proposed technology is a biocompatible and biodegradable gel enhancing axonal growth and nerve regeneration. It is composed of a complex of substances comprising transparent, highly viscous gel resembling the extracellular matrix that is almost impermeable to liquids and gasses, flexible, elastic, malleable, and adaptable to various shapes and formats. Preclinical study on rat model of peripheral nerve injury showed that GRG enhanced nerve regeneration when placed in nerve conduits, enabling recovery of massive nerve loss, previously unbridgeable, and enabled nerve regeneration at least as good as with autologous nerve graft “gold standard” treatment. Shimon Rochkind and Zvi Nevo Copyright © 2014 Shimon Rochkind and Zvi Nevo. All rights reserved. Improvements in Memory after Medial Septum Stimulation Are Associated with Changes in Hippocampal Cholinergic Activity and Neurogenesis Wed, 02 Jul 2014 06:23:55 +0000 Deep brain stimulation (DBS) has been found to have therapeutic effects in patients with dementia, but DBS mechanisms remain elusive. To provide evidence for the effectiveness of DBS as a treatment for dementia, we performed DBS in a rat model of dementia with intracerebroventricular administration of 192 IgG-saporins. We utilized four groups of rats, group 1, unlesioned control; group 2, cholinergic lesion; group 3, cholinergic lesion plus medial septum (MS) electrode implantation (sham stimulation); group 4, cholinergic lesions plus MS electrode implantation and stimulation. During the probe test in the water maze, performance of the lesion group decreased for measures of time spent and the number of swim crossings over the previous platform location. Interestingly, the stimulation group showed an equivalent performance to the normal group on all measures. And these are partially reversed by the electrode implantation. Acetylcholinesterase activity in the hippocampus was decreased in lesion and implantation groups, whereas activity in the stimulation group was not different from the normal group. Hippocampal neurogenesis was increased in the stimulation group. Our results revealed that DBS of MS restores spatial memory after damage to cholinergic neurons. This effect is associated with an increase in hippocampal cholinergic activity and neurogenesis. Da Un Jeong, Ji Eun Lee, Sung Eun Lee, Won Seok Chang, Sung June Kim, and Jin Woo Chang Copyright © 2014 Da Un Jeong et al. All rights reserved. ATP Release through Lysosomal Exocytosis from Peripheral Nerves: The Effect of Lysosomal Exocytosis on Peripheral Nerve Degeneration and Regeneration after Nerve Injury Mon, 30 Jun 2014 12:11:54 +0000 Studies have shown that lysosomal activation increases in Schwann cells after nerve injury. Lysosomal activation is thought to promote the engulfment of myelin debris or fragments of injured axons in Schwann cells during Wallerian degeneration. However, a recent interpretation of lysosomal activation proposes a different view of the phenomenon. During Wallerian degeneration, lysosomes become secretory vesicles and are activated for lysosomal exocytosis. The lysosomal exocytosis triggers adenosine 5′-triphosphate (ATP) release from peripheral neurons and Schwann cells during Wallerian degeneration. Exocytosis is involved in demyelination and axonal degradation, which facilitate nerve regeneration following nerve degeneration. At this time, released ATP may affect the communication between cells in peripheral nerves. In this review, our description of the relationship between lysosomal exocytosis and Wallerian degeneration has implications for the understanding of peripheral nerve degenerative diseases and peripheral neuropathies, such as Charcot-Marie-Tooth disease or Guillain-Barré syndrome. Junyang Jung, Hyun Woo Jo, Hyunseob Kwon, and Na Young Jeong Copyright © 2014 Junyang Jung et al. All rights reserved. Therapeutically Targeting Neuroinflammation and Microglia after Acute Ischemic Stroke Wed, 25 Jun 2014 05:03:51 +0000 Inflammation has a pivotal role in the pathogenesis of ischemic stroke, and recent studies posit that inflammation acts as a double-edged sword, not only detrimentally augmenting secondary injury, but also potentially promoting recovery. An initial event of inflammation in ischemic stroke is the activation of microglia, leading to production of both pro- and anti-inflammatory mediators acting through multiple receptor signaling pathways. In this review, we discuss the role of microglial mediators in acute ischemic stroke and elaborate on preclinical and clinical studies focused on microglia in stroke models. Understanding how microglia can lead to both pro- and anti-inflammatory responses may be essential to implement therapeutic strategies using immunomodulatory interventions in ischemic stroke. Youngjeon Lee, Sang-Rae Lee, Sung S. Choi, Hyeon-Gu Yeo, Kyu-Tae Chang, and Hong J. Lee Copyright © 2014 Youngjeon Lee et al. All rights reserved. Telemonitoring with respect to Mood Disorders and Information and Communication Technologies: Overview and Presentation of the PSYCHE Project Tue, 24 Jun 2014 12:01:55 +0000 This paper reviews what we know about prediction in relation to mood disorders from the perspective of clinical, biological, and physiological markers. It then also presents how information and communication technologies have developed in the field of mood disorders, from the first steps, for example, the transition from paper and pencil to more sophisticated methods, to the development of ecological momentary assessment methods and, more recently, wearable systems. These recent developments have paved the way for the use of integrative approaches capable of assessing multiple variables. The PSYCHE project stands for Personalised monitoring SYstems for Care in mental HEalth. Hervé Javelot, Anne Spadazzi, Luisa Weiner, Sonia Garcia, Claudio Gentili, Markus Kosel, and Gilles Bertschy Copyright © 2014 Hervé Javelot et al. All rights reserved. Evidence of Inflammatory System Involvement in Parkinson’s Disease Tue, 24 Jun 2014 12:01:14 +0000 Parkinson’s disease (PD) is a chronic neurodegenerative disease underpinned by both genetic and environmental etiologic factors. Recent findings suggest that inflammation may be a pathogenic factor in the onset and progression of both familial and sporadic PD. Understanding the precise role of inflammatory factors in PD will likely lead to understanding of how the disease arises. In vivo evidence for inflammation in PD includes dysregulated molecular mediators such as cytokines, complement system and its receptors, resident microglial activation, peripheral immune cells invasion, and altered composition and phenotype of peripheral immune cells. The growing awareness of these factors has prompted novel approaches to modulate the immune system, although it remains whether these approaches can be used in humans. Influences of ageing and differential exposure to environmental agents suggest potential host-pathogen specific pathophysiologic factors. There is a clear need for research to further unravel the pathophysiologic role of immunity in PD, with the potential of developing new therapeutic targets for this debilitating condition. Yinxia Chao, Siew Cheng Wong, and Eng King Tan Copyright © 2014 Yinxia Chao et al. All rights reserved. An In Vivo Microdialysis Study of FLZ Penetration through the Blood-Brain Barrier in Normal and 6-Hydroxydopamine Induced Parkinson’s Disease Model Rats Mon, 23 Jun 2014 00:00:00 +0000 FLZ (N-[2-(4-hydroxy-phenyl)-ethyl]-2-(2,5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide) is a novel synthetic squamosamide derivative and a potential anti-Parkinson’s disease (PD) agent. The objective of the present study was to investigate the penetration of free FLZ across the BBB and the effects of P-gp inhibition on FLZ transport in normal and 6-hydroxydopamine (6-OHDA) induced PD model rats. In vivo microdialysis was used to collect FLZ containing brain and blood dialysates following intravenous (i.v.) drug administration either with or without pretreatment with the specific P-gp inhibitor, zosuquidar trihydrochloride (zosuquidar·3HCl). A sensitive, rapid, and reliable ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technique was developed and validated to quantitate free FLZ levels in the dialysates. No significant differences were observed in the brain/blood FLZ area under the concentration-time curve (AUC) ratio between normal and PD model rats. However, pretreatment with zosuquidar·3HCl markedly increased the AUC ratio in both rat models. In addition, FLZ penetration was similar in zosuquidar·3HCl-pretreated normal and PD rats. These results suggest that P-gp inhibition increases BBB permeability to FLZ, thereby supporting the hypothesis that P-gp normally restricts FLZ transfer to the brain. These findings could provide reference data for future clinical trials and may aid investigation of the BBB permeability of other CNS-active substances. Jinfeng Hou, Qian Liu, Yingfei Li, Hua Sun, and Jinlan Zhang Copyright © 2014 Jinfeng Hou et al. All rights reserved. Chronic Dietary Supplementation of 4% Figs on the Modification of Oxidative Stress in Alzheimer’s Disease Transgenic Mouse Model Thu, 19 Jun 2014 08:24:02 +0000 We assessed the changes in the plasma Aβ, oxidative stress/antioxidants, and membrane bound enzymes in the cerebral cortex and hippocampus of Alzheimer’s disease (AD) transgenic mice (Tg2576) after dietary supplementation of Omani figs fruits for 15 months along with spatial memory and learning test. AD Tg mice on control diet without figs showed significant impairment in spatial learning ability compared to the wild-type mice on same diet and figs fed Tg mice as well. Significant increase in oxidative stress and reduced antioxidant status were observed in AD Tg mice. 4% figs treated AD Tg mice significantly attenuated oxidative damage, as evident by decreased lipid peroxidation and protein carbonyls and restoration of antioxidant status. Altered activities of membrane bound enzymes (Na+ K+ ATPase and acetylcholinesterase (AChE)) in AD Tg mice brain regions and was restored by figs treatment. Further, figs supplementation might be able to decrease the plasma levels of Aβ (1–40, 1–42) significantly in Tg mice suggesting a putative delay in the formation of plaques, which might be due to the presence of high natural antioxidants in figs. But this study warrants further extensive investigation to find a novel lead for a therapeutic target for AD from figs. Selvaraju Subash, Musthafa Mohamed Essa, Abdullah Al-Asmi, Samir Al-Adawi, and Ragini Vaishnav Copyright © 2014 Selvaraju Subash et al. All rights reserved. Poststroke Neuropsychiatric Symptoms: Relationships with IL-17 and Oxidative Stress Wed, 18 Jun 2014 09:37:15 +0000 Stroke variably activates interleukin- (IL-) 17 expression, reduces regulatory T cells, and induces oxidative stress, which may support neurodegeneration. Ischemic stroke patients were screened for depressive symptoms (Center for Epidemiological Studies Depression (CES-D)) and cognitive status (Mini Mental State Examination). Proinflammatory cytokines (IL-17, IL-23, and interferon- [IFN-] γ), anti-inflammatory cytokine IL-10, and lipid hydroperoxide (LPH), a measure of oxidative stress, were assayed from fasting serum. Of 47 subjects (age 71.8 ± 14.4 years, 36% female), 19 had depressive symptoms (CES-D ≥ 16), which was associated with poorer cognitive status (, ). IL-17 concentrations did not differ between subjects with and without depressive symptoms (, ); however, IL-17 was associated with poorer cognitive status in subjects with depressive symptoms (, ). In those subjects with depressive symptoms, IL-17 was associated with higher LPH (, ) and lower IL-10 (, ), but not in those without. In conclusion, poststroke depressive symptoms may be associated with cognitive vulnerability to IL-17 related pathways, involving an imbalance between proinflammatory and anti-inflammatory activity and increased oxidative stress. W. Swardfager, N. Herrmann, A. C. Andreazza, R. H. Swartz, M. M. Khan, S. E. Black, and K. L. Lanctôt Copyright © 2014 W. Swardfager et al. All rights reserved. Multipotent Neural Crest Stem Cell-Like Cells from Rat Vibrissa Dermal Papilla Induce Neuronal Differentiation of PC12 Cells Wed, 18 Jun 2014 07:38:52 +0000 Bone marrow mesenchymal stem cells (BMSCs) transplants have been approved for treating central nervous system (CNS) injuries and diseases; however, their clinical applications are limited. Here, we model the therapeutic potential of dermal papilla cells (DPCs) in vitro. DPCs were isolated from rat vibrissae and characterized by immunocytofluorescence, RT-PCR, and multidifferentiation assays. We examined whether these cells could secrete neurotrophic factors (NTFs) by using cocultures of rat pheochromocytoma cells (PC12) with conditioned medium and ELISA assay. DPCs expressed Sox10, P75, Nestin, Sox9, and differentiated into adipocytes, osteoblasts, smooth muscle cells, and neurons under specific inducing conditions. The DPC-conditioned medium (DPC-CM) induced neuronal differentiation of PC12 cells and promoted neurite outgrowth. Results of ELISA assay showed that compared to BMSCs, DPCs secreted more brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). Moreover, we observed that, compared with the total DPC population, sphere-forming DPCs expressed higher levels of Nestin and P75 and secreted greater amounts of GDNF. The DPCs from craniofacial hair follicle papilla may be a new and promising source for treating CNS injuries and diseases. Meiying Li, Jin Yu Liu, Shichao Wang, Hao Xu, Lifeng Cui, Shuang Lv, Jinying Xu, Shutong Liu, Guangfan Chi, and Yulin Li Copyright © 2014 Meiying Li et al. All rights reserved. CNB-001 a Novel Curcumin Derivative, Guards Dopamine Neurons in MPTP Model of Parkinson’s Disease Tue, 17 Jun 2014 08:02:56 +0000 Copious experimental and postmortem studies have shown that oxidative stress mediated degeneration of nigrostriatal dopaminergic neurons underlies Parkinson’s disease (PD) pathology. CNB-001, a novel pyrazole derivative of curcumin, has recently been reported to possess various neuroprotective properties. This study was designed to investigate the neuroprotective mechanism of CNB-001 in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rodent model of PD. Administration of MPTP (30 mg/kg for four consecutive days) exacerbated oxidative stress and motor impairment and reduced tyrosine hydroxylase (TH), dopamine transporter, and vesicular monoamine transporter 2 (VMAT2) expressions. Moreover, MPTP induced ultrastructural changes such as distorted cristae and mitochondrial enlargement in substantia nigra and striatum region. Pretreatment with CNB-001 (24 mg/kg) not only ameliorated behavioral anomalies but also synergistically enhanced monoamine transporter expressions and cosseted mitochondria by virtue of its antioxidant action. These findings support the neuroprotective property of CNB-001 which may have strong therapeutic potential for treatment of PD. Richard L. Jayaraj, Namasivayam Elangovan, Krishnan Manigandan, Sonu Singh, and Shubha Shukla Copyright © 2014 Richard L. Jayaraj et al. All rights reserved. Challenges for Nerve Repair Using Chitosan-Siloxane Hybrid Porous Scaffolds Tue, 17 Jun 2014 06:36:23 +0000 The treatment of peripheral nerve injuries remains one of the greatest challenges of neurosurgery, as functional recover is rarely satisfactory in these patients. Recently, biodegradable nerve guides have shown great potential for enhancing nerve regeneration. A major advantage of these nerve guides is that no foreign material remains after the device has fulfilled its task, which spares a second surgical intervention. Recently, we studied peripheral nerve regeneration using chitosan-γ-glycidoxypropyltrimethoxysilane (chitosan-GPTMS) porous hybrid membranes. In our studies, these porous membranes significantly improved nerve fiber regeneration and functional recovery in rat models of axonotmetic and neurotmetic sciatic nerve injuries. In particular, the number of regenerated myelinated nerve fibers and myelin thickness were significantly higher in rat treated with chitosan porous hybrid membranes, whether or not they were used in combination with mesenchymal stem cells isolated from the Wharton’s jelly of the umbilical cord. In this review, we describe our findings on the use of chitosan-GPTMS hybrids for nerve regeneration. Yuki Shirosaki, Satoshi Hayakawa, Akiyoshi Osaka, Maria A. Lopes, José D. Santos, Stefano Geuna, and Ana C. Mauricio Copyright © 2014 Yuki Shirosaki et al. All rights reserved. Chronic Neuroinflammation in Alzheimer’s Disease: New Perspectives on Animal Models and Promising Candidate Drugs Mon, 16 Jun 2014 12:59:07 +0000 Chronic neuroinflammation is now considered one of the major factors in the pathogenesis of Alzheimer’s disease (AD). However, the most widely used transgenic AD models (overexpressing mutated forms of amyloid precursor protein, presenilin, and/or tau) do not demonstrate the degree of inflammation, neurodegeneration (particularly of the cholinergic system), and cognitive decline that is comparable with the human disease. Hence a more suitable animal model is needed to more closely mimic the resulting cognitive decline and memory loss in humans in order to investigate the effects of neuroinflammation on neurodegeneration. One of these models is the glial fibrillary acidic protein-interleukin 6 (GFAP-IL6) mouse, in which chronic neuroinflammation triggered constitutive expression of the cytokine interleukin-6 (IL-6) in astrocytes. These transgenic mice show substantial and progressive neurodegeneration as well as a decline in motor skills and cognitive function, starting from 6 months of age. This animal model could serve as an excellent tool for drug discovery and validation in vivo. In this review, we have also selected three potential anti-inflammatory drugs, curcumin, apigenin, and tenilsetam, as candidate drugs, which could be tested in this model. Christopher Millington, Sandra Sonego, Niloo Karunaweera, Alejandra Rangel, Janice R. Aldrich-Wright, Iain L. Campbell, Erika Gyengesi, and Gerald Münch Copyright © 2014 Christopher Millington et al. All rights reserved. Adrenomedullin Deficiency and Aging Exacerbate Ischemic White Matter Injury after Prolonged Cerebral Hypoperfusion in Mice Mon, 16 Jun 2014 09:08:36 +0000 Adrenomedullin was originally isolated from pheochromocytoma cells and reduces insulin resistance by decreasing oxidative stress. White matter lesions induced by aging and hyperglycemia play a crucial role in cognitive impairment in poststroke patients. Here, we examine whether adrenomedullin deficiency and aging exacerbate ischemic white matter injury after prolonged cerebral hypoperfusion. Adrenomedullin heterozygous, wild-type young/aged mice were subjected to prolonged hypoperfusion. Prolonged cerebral hypoperfusion followed by immunohistochemical analysis was used to evaluate white matter injury. After prolonged hypoperfusion, white matter damage progressed in a time-dependent manner in AM+/− group compared with the wild-type group. The number of oligodendrocyte progenitor cells gradually increased after prolonged hypoperfusion, whereas oligodendrocytes decreased following a transient increase, but the ratio of increase was mild in the AM+/− group . Oxidative stress was detected in oligodendrocytes, with a larger increase in the AM+/− group . Aged mice showed the same tendency, but white matter damage was worse, especially in the aged AM+/− group. Our results demonstrated that white matter injury was increased in adrenomedullin deficiency, which induced oxidative stress. White matter injury was more exacerbated because of hyperglycemia in aged AM+/− group. Adrenomedullin may be an important target in the control of ischemic white matter injury. Yumiko Mitome-Mishima, Nobukazu Miyamoto, Ryota Tanaka, Tatsuo Shimosawa, Hidenori Oishi, Hajime Arai, Nobutaka Hattori, and Takao Urabe Copyright © 2014 Yumiko Mitome-Mishima et al. All rights reserved. Downregulation of Transketolase Activity Is Related to Inhibition of Hippocampal Progenitor Cell Proliferation Induced by Thiamine Deficiency Mon, 16 Jun 2014 06:48:29 +0000 In animal experiments, hippocampal neurogenesis and the activity of thiamine-dependent transketolase decrease markedly under conditions of thiamine deficiency. To further investigate the effect of thiamine deficiency on the proliferation of hippocampal progenitor cells (HPCs) and the potential mechanisms involved in this effect, we cultured HPCs in vitro in the absence of thiamine and found that proliferation and transketolase activity were both significantly repressed. Furthermore, specific inhibition of transketolase activity by oxythiamine strongly inhibited HPC proliferation in a dose-dependent manner. However, thiamine deficiency itself inhibited the proliferation to a greater degree than did oxythiamine. Taken together, our results suggest that modulation of transketolase activity might be one of the mechanisms by which thiamine regulates the proliferation of hippocampal progenitor cells. Yanling Zhao, Yiying Wu, Haolu Hu, Jinghui Cai, Min Ning, Xiushi Ni, and Chunjiu Zhong Copyright © 2014 Yanling Zhao et al. All rights reserved. Ceftriaxone, a Beta-Lactam Antibiotic, Modulates Apoptosis Pathways and Oxidative Stress in a Rat Model of Neuropathic Pain Mon, 16 Jun 2014 05:36:43 +0000 Purpose. In our previous study, ceftriaxone, a beta-lactam antibiotic, elicited antinociceptive effects in the chronic constriction injury (CCI) of neuropathic pain. In this study, we assessed apoptosis and oxidative stress in the spinal cord of neuropathic rats treated with ceftriaxone. Methods. 45 male Wistar rats were divided as naïve, sham, normal saline-treated CCI rats, and CCI animals treated with the effective dose of ceftriaxone. Involvement of Bax, Bcl2, and caspases 3 and 9, important contributors of programmed cell death (apoptosis), was determined using western blotting at days 3 and 7. The markers of oxidative stress including malondialdehyde (MDA) and reduced glutathione (GSH) were measured on days 3 and 7. Results. Increased Bax/Bcl2 ratio and cleaved active forms of caspases 3 and 9 were observed in the spinal cord of CCI rats on day 3. Ceftriaxone attenuated the increased levels of Bax and cleaved forms of caspases 3 and 9, while it increased Bcl2 levels. Bax and active forms of caspases declined by day 7. Consequently, comparison among groups showed no difference at this time. CCI enhanced MDA and decreased GSH on days 3 and 7, while ceftriaxone protected against the CCI-induced oxidative stress. Conclusion. Our results suggest that ceftriaxone, an upregulator/activator of GLT1, could concomitantly reduce oxidative stress and apoptosis and producing its new analogs lacking antimicrobial activity may represent a novel approach for neuropathic pain treatment. Bahareh Amin, Valiollah Hajhashemi, Khalil Abnous, and Hossein Hosseinzadeh Copyright © 2014 Bahareh Amin et al. All rights reserved. EEG Oscillatory Phase-Dependent Markers of Corticospinal Excitability in the Resting Brain Wed, 11 Jun 2014 12:07:13 +0000 Functional meaning of oscillatory brain activity in various frequency bands in the human electroencephalogram (EEG) is increasingly researched. While most research focuses on event-related changes of brain activity in response to external events there is also increasing interest in internal brain states influencing information processing. Several studies suggest amplitude changes of EEG oscillatory activity selectively influencing cortical excitability, and more recently it was shown that phase of EEG activity (instantaneous phase) conveys additional meaning. Here we review this field with many conflicting findings and further investigate whether corticospinal excitability in the resting brain is dependent on a specific spontaneously occurring brain state reflected by amplitude and instantaneous phase of EEG oscillations. We applied single pulse transcranial magnetic stimulation (TMS) over the left sensorimotor cortex, while simultaneously recording ongoing oscillatory activity with EEG. Results indicate that brain oscillations reflect rapid, spontaneous fluctuations of cortical excitability. Instantaneous phase but not amplitude of oscillations at various frequency bands at stimulation site at the time of TMS-pulse is indicative for brain states associated with different levels of excitability (defined by size of the elicited motor evoked potential). These results are further evidence that ongoing brain oscillations directly influence neural excitability which puts further emphasis on their role in orchestrating neuronal firing in the brain. Barbara Berger, Tamas Minarik, Gianpiero Liuzzi, Friedhelm C. Hummel, and Paul Sauseng Copyright © 2014 Barbara Berger et al. All rights reserved. Diffusion Tensor Histogram Analysis of Pediatric Diffuse Intrinsic Pontine Glioma Wed, 11 Jun 2014 11:49:46 +0000 Purpose. To evaluate tumor structure in children with diffuse intrinsic pontine glioma (DIPG) using histogram analyses of mean diffusivity (MD), determine potential treatment and corticosteroid-related effects on MD, and monitor changes in MD distributions over time. Materials and Methods. DTI was performed on a 1.5T GE scanner. Regions of interest included the entire FLAIR-defined tumor. MD data were used to calculate histograms. Patterns in MD distributions were evaluated and fitted using a two-normal mixture model. Treatment-related effects were evaluated using the statistic for linear mixed models and Cox proportional hazards models. Results. 12 patients with DIPG underwent one or more DTI exams. MD histogram distributions varied among patients. Over time, histogram peaks became shorter and broader (). Two-normal mixture fitting revealed large lower curve proportions that were not associated with treatment response or outcome. Corticosteroid use affected MD histograms and was strongly associated with larger, sharper peaks (, ). Conclusions. MD histograms of pediatric DIPG show significant interpatient and intratumoral differences and quantifiable changes in tumor structure over time. Corticosteroids greatly affected MD and must be considered a confounding factor when interpreting MD results in the context of treatment response. Emilie A. Steffen-Smith, Joelle E. Sarlls, Carlo Pierpaoli, Joanna H. Shih, Robyn S. Bent, Lindsay Walker, and Katherine E. Warren Copyright © 2014 Emilie A. Steffen-Smith et al. All rights reserved. Simvastatin Combined with Antioxidant Attenuates the Cerebral Vascular Endothelial Inflammatory Response in a Rat Traumatic Brain Injury Wed, 11 Jun 2014 11:05:13 +0000 Traumatic brain injury (TBI) leads to important and deleterious neuroinflammation, as evidenced by indicators such as edema, cytokine production, induction of nitric oxide synthase, and leukocyte infiltration. After TBI, cerebral vascular endothelial cells play a crucial role in the pathogenesis of inflammation. In our previous study, we proved that simvastatin could attenuate cerebral vascular endothelial inflammatory response in a rat traumatic brain injury. This purpose of this study was to determine whether simvastatin combined with an antioxidant could produce the same effect or greater and to examine affected surrogate biomarkers for the neuroinflammation after traumatic brain injury in rat. In our study, cortical contusions were induced, and the effect of acute and continuous treatment of simvastatin and vitamin C on behavior and inflammation in adult rats following experimental TBI was evaluated. The results demonstrated that simvastatin combined with an antioxidant could provide neuroprotection and it may be attributed to a dampening of cerebral vascular endothelial inflammatory response. Kuo-Wei Wang, Hao-Kuang Wang, Han-Jung Chen, Po-Chou Liliang, Cheng-Loong Liang, Yu-Duan Tsai, Chung-Lung Cho, and Kang Lu Copyright © 2014 Kuo-Wei Wang et al. All rights reserved. Protective Effects of Borago officinalis Extract on Amyloid β-Peptide(25–35)-Induced Memory Impairment in Male Rats: A Behavioral Study Wed, 11 Jun 2014 09:28:19 +0000 Alzheimer’s disease (AD) is a neurodegenerative disorder and most common form of dementia that leads to memory impairment. In the present study we have examined the protective effects of Borago officinalis (borage) extract on Amyloid β (Aβ)-Induced memory impairment. Wistar male rats received intrahippocampal (IHP) injection of the Aβ(25–35) and borage extract throughout gestation (100 mg/kg). Learning and memory functions in the rats were examined by the passive avoidance and the Morris water maze (MWM) tasks. Finally, the antioxidant capacity of hippocampus was measured using ferric ion reducing antioxidant power (FRAP) assay. The results showed that Aβ(25–35) impaired step-through latency and time in dark compartment in passive avoidance task. In the MWM, Aβ(25–35) significantly increased escape latency and traveled distance. Borage administration attenuated the Aβ-induced memory impairment in both the passive avoidance and the MWM tasks. Aβ induced a remarkable decrease in antioxidant power (FRAP value) of hippocampus and borage prevented the decrease of the hippocampal antioxidant status. This data suggests that borage could improve the learning impairment and oxidative damage in the hippocampal tissue following Aβ treatment and that borage consumption may lead to an improvement of AD-induced cognitive dysfunction. Fatemeh Ghahremanitamadon, Siamak Shahidi, Somayeh Zargooshnia, Ali Nikkhah, Akram Ranjbar, and Sara Soleimani Asl Copyright © 2014 Fatemeh Ghahremanitamadon et al. All rights reserved. Fear-Potentiated Behaviour Is Modulated by Central Amygdala Angiotensin II Receptors Stimulation Mon, 09 Jun 2014 12:47:42 +0000 Central nucleus of the amygdala (CeA) is one of the most important regulatory centres for the emotional processes. Among the different neurotransmitter systems present in this nucleus, AT1 receptors have been also found, but their role in the generation and modulation of emotions is not fully understood. The present work evaluated the effect of intra-amygdalar injection of losartan (AT1 receptor antagonist) and angiotensin II (Ang II) in the anxiety state induced by fear-potentiated plus maze in male Wistar rats. Fear in the elevated plus maze can be potentiated by prior inescapable footshock stress. The decrease in the time spent in the open arms induced by the inescapable footshock was totally prevented by losartan (4 pmol) administration in CeA. It was also found that Ang II (48 fmol) administration decreased the time spent in the open arms in animals with or without previous footshock exposure. The locomotor activity and grooming behaviour were also evaluated. The results obtained from the different parameters analyzed allowed us to conclude that the Ang II AT1 receptors in CeA are involved in the anxiety state induced by stress in the fear-potentiated plus-maze behaviour. Maria de los Angeles Marinzalda, Pablo A. Pérez, Pascual A. Gargiulo, Brenda S. Casarsa, Claudia Bregonzio, and Gustavo Baiardi Copyright © 2014 Maria de los Angeles Marinzalda et al. All rights reserved. Rodent Models of Depression: Neurotrophic and Neuroinflammatory Biomarkers Thu, 05 Jun 2014 07:37:20 +0000 Rodent models are an indispensable tool for studying etiology and progress of depression. Since interrelated systems of neurotrophic factors and cytokines comprise major regulatory mechanisms controlling normal brain plasticity, impairments of these systems form the basis for development of cerebral pathologies, including mental diseases. The present review focuses on the numerous experimental rodent models of depression induced by different stress factors (exteroceptive and interoceptive) during early life (including prenatal period) or adulthood, giving emphasis to the data on the changes of neurotrophic factors and neuroinflammatory indices in the brain. These parameters are closely related to behavioral depression-like symptoms and impairments of neuronal plasticity and are both gender- and genotype-dependent. Stress-related changes in expression of neurotrophins and cytokines in rodent brain are region-specific. Some contradictory data reported by different groups may be a consequence of differences of stress paradigms or their realization in different laboratories. Like all experimental models, stress-induced depression-like conditions are experimental simplification of clinical depression states; however, they are suitable for understanding the involvement of neurotrophic factors and cytokines in the pathogenesis of the disease—a goal unachievable in the clinical reality. These major regulatory systems may be important targets for therapeutic measures as well as for development of drugs for treatment of depression states. Mikhail Stepanichev, Nikolay N. Dygalo, Grigory Grigoryan, Galina T. Shishkina, and Natalia Gulyaeva Copyright © 2014 Mikhail Stepanichev et al. All rights reserved. Advances in Neurovascular Treatments Thu, 05 Jun 2014 06:59:11 +0000 Robert M. Starke, Stephen J. Monteith, Nohra Chalouhi, Dale Ding, Ricky Medel, David Hasan, and Aaron S. Dumont Copyright © 2014 Robert M. Starke et al. All rights reserved. The Proximal Medial Sural Nerve Biopsy Model: A Standardised and Reproducible Baseline Clinical Model for the Translational Evaluation of Bioengineered Nerve Guides Mon, 02 Jun 2014 09:10:54 +0000 Autologous nerve transplantation (ANT) is the clinical gold standard for the reconstruction of peripheral nerve defects. A large number of bioengineered nerve guides have been tested under laboratory conditions as an alternative to the ANT. The step from experimental studies to the implementation of the device in the clinical setting is often substantial and the outcome is unpredictable. This is mainly linked to the heterogeneity of clinical peripheral nerve injuries, which is very different from standardized animal studies. In search of a reproducible human model for the implantation of bioengineered nerve guides, we propose the reconstruction of sural nerve defects after routine nerve biopsy as a first or baseline study. Our concept uses the medial sural nerve of patients undergoing diagnostic nerve biopsy (≥2 cm). The biopsy-induced nerve gap was immediately reconstructed by implantation of the novel microstructured nerve guide, Neuromaix, as part of an ongoing first-in-human study. Here we present (i) a detailed list of inclusion and exclusion criteria, (ii) a detailed description of the surgical procedure, and (iii) a follow-up concept with multimodal sensory evaluation techniques. The proximal medial sural nerve biopsy model can serve as a preliminarynature of the injuries or baseline nerve lesion model. In a subsequent step, newly developed nerve guides could be tested in more unpredictable and challenging clinical peripheral nerve lesions (e.g., following trauma) which have reduced comparability due to the different nature of the injuries (e.g., site of injury and length of nerve gap). Ahmet Bozkurt, Sabien G. A. van Neerven, Kristl G. Claeys, Dan mon O'Dey, Angela Sudhoff, Gary A. Brook, Bernd Sellhaus, Jörg B. Schulz, Joachim Weis, and Norbert Pallua Copyright © 2014 Ahmet Bozkurt et al. All rights reserved. A Tool for Balance Control Training Using Muscle Synergies and Multimodal Interfaces Thu, 29 May 2014 09:18:43 +0000 Balance control plays a key role in neuromotor rehabilitation after stroke or spinal cord injuries. Computerized dynamic posturography (CDP) is a classic technological tool to assess the status of balance control and to identify potential disorders. Despite the more accurate diagnosis generated by these tools, the current strategies to promote rehabilitation are still limited and do not take full advantage of the technologies available. This paper presents a novel balance training platform which combines a CDP device made from low-cost interfaces, such as the Nintendo Wii Balance Board and the Microsoft Kinect. In addition, it integrates a custom electrical stimulator that uses the concept of muscle synergies to promote natural interaction. The aim of the platform is to support the exploration of innovative multimodal therapies. Results include the technical validation of the platform using mediolateral and anteroposterior sways as basic balance training therapies. D. Galeano, F. Brunetti, D. Torricelli, S. Piazza, and J. L. Pons Copyright © 2014 D. Galeano et al. All rights reserved. Evaluation of Plant Phenolic Metabolites as a Source of Alzheimer's Drug Leads Thu, 29 May 2014 06:25:52 +0000 Epidemiological studies have proven an association between consumption of polyphenols and prevention of Alzheimer’s disease, the most common form of dementia characterized by extracellular deposition of amyloid beta plaques. The aim of this study is pharmacological screening of the aqueous alcohol extract of Markhamia platycalyx leaves, Schotia brachypetala leaves and stalks, and piceatannol compared to aqueous alcohol extract of Camellia sinensis leaves as potential Alzheimer’s disease drugs. LC-HRESI(-ve)-MSn was performed to identify phenolics’ profile of Schotia brachypetala stalks aqueous alcohol extract and revealed ten phenolic compounds as first report: daidzein, naringin, procyanidin isomers, procyanidin dimer gallate, quercetin 3-O-rhamnoside, quercetin 3-O-glucuronide, quercetin hexose gallic acid, quercetin hexose protocatechuic acid, and ellagic acid. Alzheimer’s disease was induced by a single intraperitoneal injection of LPS. Adult male Swiss albino mice were divided into groups of 8–10 mice each receiving treatment for six days. In vivo behavioral tests (Y maze and object recognition) and in vitro estimation of amyloid beta 42 by ELISA showed significant differences between results of treated and nontreated animals. Yara Hassaan, Heba Handoussa, Ahmed H. El-Khatib, Michael W. Linscheid, Nesrine El Sayed, and Nahla Ayoub Copyright © 2014 Yara Hassaan et al. All rights reserved. Adaptive Personalized Training Games for Individual and Collaborative Rehabilitation of People with Multiple Sclerosis Wed, 28 May 2014 08:07:48 +0000 Any rehabilitation involves people who are unique individuals with their own characteristics and rehabilitation needs, including patients suffering from Multiple Sclerosis (MS). The prominent variation of MS symptoms and the disease severity elevate a need to accommodate the patient diversity and support adaptive personalized training to meet every patient’s rehabilitation needs. In this paper, we focus on integrating adaptivity and personalization in rehabilitation training for MS patients. We introduced the automatic adjustment of difficulty levels as an adaptation that can be provided in individual and collaborative rehabilitation training exercises for MS patients. Two user studies have been carried out with nine MS patients to investigate the outcome of this adaptation. The findings showed that adaptive personalized training trajectories have been successfully provided to MS patients according to their individual training progress, which was appreciated by the patients and the therapist. They considered the automatic adjustment of difficulty levels to provide more variety in the training and to minimize the therapists involvement in setting up the training. With regard to social interaction in the collaborative training exercise, we have observed some social behaviors between the patients and their training partner which indicated the development of social interaction during the training. Johanna Renny Octavia and Karin Coninx Copyright © 2014 Johanna Renny Octavia and Karin Coninx. All rights reserved. Conditioned Media from Human Adipose Tissue-Derived Mesenchymal Stem Cells and Umbilical Cord-Derived Mesenchymal Stem Cells Efficiently Induced the Apoptosis and Differentiation in Human Glioma Cell Lines In Vitro Tue, 27 May 2014 11:25:41 +0000 Human mesenchymal stem cells (MSCs) have an intrinsic property for homing towards tumor sites and can be used as tumor-tropic vectors for tumor therapy. But very limited studies investigated the antitumor properties of MSCs themselves. In this study we investigated the antiglioma properties of two easily accessible MSCs, namely, human adipose tissue-derived mesenchymal stem cells (ASCs) and umbilical cord-derived mesenchymal stem cells (UC-MSCs). We found (1) MSC conditioned media can significantly inhibit the growth of human U251 glioma cell line; (2) MSC conditioned media can significantly induce apoptosis in human U251 cell line; (3) real-time PCR experiments showed significant upregulation of apoptotic genes of both caspase-3 and caspase-9 and significant downregulation of antiapoptotic genes such as survivin and XIAP after MSC conditioned media induction in U 251 cells; (4) furthermore, MSCs conditioned media culture induced rapid and complete differentiation in U251 cells. These results indicate MSCs can efficiently induce both apoptosis and differentiation in U251 human glioma cell line. Whereas UC-MSCs are more efficient for apoptosis induction than ASCs, their capability of differentiation induction is not distinguishable from each other. Our findings suggest MSCs themselves have favorable antitumor characteristics and should be further explored in future glioma therapy. Chao Yang, Deqiang Lei, Weixiang Ouyang, Jinghua Ren, Huiyu Li, Jingqiong Hu, and Shiang Huang Copyright © 2014 Chao Yang et al. All rights reserved. Association between Severe Upper Limb Spasticity and Brain Lesion Location in Stroke Patients Sun, 25 May 2014 09:37:56 +0000 Association between the site of brain injury and poststroke spasticity is poorly understood. The present study investigated whether lesion analysis could document brain regions associated with the development of severe upper limb poststroke spasticity. A retrospective analysis was conducted on 39 chronic stroke patients. Spasticity was assessed at the affected upper limb with the modified Ashworth scale (shoulder, elbow, wrist, and fingers). Brain lesions were traced from magnetic resonance imaging performed within the first 7 days after stroke and region of interest images were generated. The association between severe upper limb spasticity (modified Ashworth scale ≥2) and lesion location was determined with the voxel-based lesion-symptom mapping method implemented in MRIcro software. Colored maps representing the statistics were generated and overlaid onto the automated anatomical labeling and the Johns Hopkins University white matter templates provided with MRIcron. Thalamic nuclei were identified with the Talairach Daemon software. Injuries to the insula, the thalamus, the basal ganglia, and white matter tracts (internal capsule, corona radiata, external capsule, and superior longitudinal fasciculus) were significantly associated with severe upper limb poststroke spasticity. Further advances in our understanding of the neural correlates of spasticity may lead to early targeted rehabilitation when key regions are damaged. Alessandro Picelli, Stefano Tamburin, Francesca Gajofatto, Giampietro Zanette, Marialuigia Praitano, Leopold Saltuari, Claudio Corradini, and Nicola Smania Copyright © 2014 Alessandro Picelli et al. All rights reserved. Knockdown of AKT3 (PKBγ) and PI3KCA Suppresses Cell Viability and Proliferation and Induces the Apoptosis of Glioblastoma Multiforme T98G Cells Thu, 22 May 2014 09:38:38 +0000 Glioblastoma multiforme (GBM) is the most malignant and invasive human brain tumor that is difficult to treat and has a very poor prognosis. Thus, new therapeutic strategies that target GBM are urgently needed. The PI3K/AKT/PTEN signaling pathway is frequently deregulated in a wide range of cancers. The present study was designed to examine the inhibitory effect of AKT3 or PI3KCA siRNAs on GBM cell growth, viability, and proliferation.T98G cells were transfected with AKT3 and/or PI3KCA siRNAs. AKT3 and PI3KCA protein-positive cells were identified using FC and Western blotting. The influence of specific siRNAs on T98G cell viability, proliferation, cell cycle, and apoptosis was evaluated as well using FC. Alterations in the mRNA expression of AKT3, PI3KCA, and apoptosis-related genes were analyzed using QRT-PCR. Knockdown of AKT3 and/or PI3KCA genes in T98G cells led to a significant reduction in cell viability, the accumulation of subG1-phase cells and, a reduced fraction of cells in the S and G2/M phases. Additionally, statistically significant differences in the BAX/BCL-2 ratio and an increased percentage of apoptotic cells were found. The siRNA-induced AKT3 and PI3KCA mRNA knockdown may offer a novel therapeutic strategy to control the growth of human GBM cells. Monika Paul-Samojedny, Renata Suchanek, Paulina Borkowska, Adam Pudełko, Aleksander Owczarek, Małgorzata Kowalczyk, Grzegorz Machnik, Anna Fila-Daniłow, and Jan Kowalski Copyright © 2014 Monika Paul-Samojedny et al. All rights reserved. Metabolic Demand and Muscle Activation during Different Forms of Bodyweight Supported Locomotion in Men with Incomplete SCI Wed, 21 May 2014 12:57:44 +0000 Body weight supported locomotor training uses neuroplasticity principles to improve recovery following a spinal cord injury (SCI). Steady state locomotion using the same body weight support (BWS) percent was compared in 7 males (42.6 4.29 years) with incomplete SCI and matched (gender, age) noninjured controls (42.7 5.4 years) using the Lokomat, Manual Treadmill, and ZeroG. The VO2000, Polar Heart Rate (HR) Monitor, and lower limb electromyography (EMG) electrodes were worn during the 2-minute sessions. Oxygen uptake (VO2) and HR were expressed as percentage of peak values obtained using progressive arm ergometry; VO2 was also expressed relative to resting metabolic equivalents (METS). Filtered EMG signals from tibialis anterior (TA), rectus femoris (RF), biceps femoris (BF), and medial gastrocnemius (MG) were normalized to ZeroG stepping. The Lokomat required 30% of VO2 peak (2METS) compared to ~54% (3METS) for Manual Treadmill and ZeroG sessions. HR was 67% of peak during Lokomat sessions compared to ~83% for Manual Treadmill and ZeroG. Muscle activation was higher in treadmill conditions compared to the ZeroG primarily due to increased BF activity. At the same level of BWS, locomotion using the Manual Treadmill or the ZeroG is more aerobically demanding than the Lokomat. Treadmill modalities encourage greater hip extensor activation compared to overground locomotion. Alyssa M. Fenuta and Audrey L. Hicks Copyright © 2014 Alyssa M. Fenuta and Audrey L. Hicks. All rights reserved. Lithium Enhances Axonal Regeneration in Peripheral Nerve by Inhibiting Glycogen Synthase Kinase 3β Activation Tue, 20 May 2014 08:55:34 +0000 Brachial plexus injury often involves traumatic root avulsion resulting in permanent paralysis of the innervated muscles. The lack of sufficient regeneration from spinal motoneurons to the peripheral nerve (PN) is considered to be one of the major causes of the unsatisfactory outcome of various surgical interventions for repair of the devastating injury. The present study was undertaken to investigate potential inhibitory signals which influence axonal regeneration after root avulsion injury. The results of the study showed that root avulsion triggered GSK-3β activation in the injured motoneurons and remaining axons in the ventral funiculus. Systemic application of a clinical dose of lithium suppressed activated GSK-3β in the lesioned spinal cord to the normal level and induced extensive axonal regeneration into replanted ventral roots. Our study suggests that GSK-3β activity is involved in negative regulation for axonal elongation and regeneration and lithium, the specific GSK-3β inhibitor, enhances motoneuron regeneration from CNS to PNS. Huanxing Su, Qiuju Yuan, Dajiang Qin, Xiaoying Yang, Wai-Man Wong, Kwok-Fai So, and Wutian Wu Copyright © 2014 Huanxing Su et al. All rights reserved. The Roles of Biomarkers of Oxidative Stress and Antioxidant in Alzheimer’s Disease: A Systematic Review Wed, 14 May 2014 09:45:15 +0000 Purpose. Oxidative stress plays an important role in the pathogenesis of Alzheimer’s disease (AD). This paper aims to examine whether biomarkers of oxidative stress and antioxidants could be useful biomarkers in AD, which might form the bases of future clinical studies. Methods. PubMed, SCOPUS, and Web of Science were systematically queried to obtain studies with available data regarding markers of oxidative stress and antioxidants from subjects with AD. Results and Conclusion. Although most studies show elevated serum markers of lipid peroxidation in AD, there is no sufficient evidence to justify the routine use of biomarkers as predictors of severity or outcome in AD. Ya-Ting Chang, Wen-Neng Chang, Nai-Wen Tsai, Chih-Cheng Huang, Chia-Te Kung, Yu-Jih Su, Wei-Che Lin, Ben-Chung Cheng, Chih-Min Su, Yi-Fang Chiang, and Cheng-Hsien Lu Copyright © 2014 Ya-Ting Chang et al. All rights reserved. Translational Neuroimaging of the Mood and Anxiety Disorders Mon, 12 May 2014 10:19:44 +0000 Su Lui, Qiyong Gong, Yong He, Georg Northoff, and John A. Sweeney Copyright © 2014 Su Lui et al. All rights reserved. Correlation of Altered Expression of the Autophagy Marker LC3B with Poor Prognosis in Astrocytoma Mon, 12 May 2014 07:03:12 +0000 Glioblastoma multiforme is one of the most serious malignant brain tumors and is characterized by resistance to chemotherapy and radiation therapy. Recent studies suggest that autophagy may play an important role not only in the regulation of cancer development and progression but also in determining the response of cancer cells to anticancer therapy. The purpose of the present study was to assess the relationship between protein expressions of two autophagy markers, LC3B and Beclin-1, with clinical parameters in astrocytoma patients. Furthermore, the expression of CD133, a marker of the cancer stem-like cells, in astrocytoma patients was also investigated. A total of 106 thin-section slides were retrospectively collected from astrocytoma patients. LC3B, but not Beclin-1, protein expression was found to significantly correlate with resistance to radiation- or chemotherapy. In addition, high intensity of LC3B staining was predictive of poor prognosis. Furthermore, survival time of patients with high-level expression in both CD133 and LC3B was significantly shorter than those with weak expression in both CD133 and LC3B. These results suggest that astrocytoma cancer stem-like cells together with enhanced autophagy may cause resistance to radiation therapy/chemotherapy and that targeting the cancer stem-like cell in astrocytoma may offer a viable therapeutic approach. Daniel Winardi, Hung-Pei Tsai, Chee-Yin Chai, Chia-Li Chung, Joon-Khim Loh, Yung-Hsiang Chen, and Ching-Liang Hsieh Copyright © 2014 Daniel Winardi et al. All rights reserved. Human Schwann Cells Seeded on a Novel Collagen-Based Microstructured Nerve Guide Survive, Proliferate, and Modify Neurite Outgrowth Sun, 11 May 2014 08:23:26 +0000 A variety of new bioartificial nerve guides have been tested preclinically for their safety and nerve regeneration supporting properties. So far, only a limited number of biomaterials have been tested in humans since the step from preclinical work to a clinical application is challenging. We here present an in vitro model with human Schwann cells (hSCs) as an intermediate step towards clinical application of the nerve guide Perimaix, a collagen-based microstructured 3D scaffold containing numerous longitudinal guidance channels for directed axonal growth. hSCs were seeded onto different prototypes of Perimaix and cultivated for 14 days. hSC adhered to the scaffold, proliferated, and demonstrated healthy Schwann cell morphology (spindle shaped cell bodies, bipolar oriented processes) not only at the surface of the material, but also in the deeper layers of the scaffold. The general well-being of the cells was quantitatively confirmed by low levels of lactate dehydrogenase release into the culture medium. Moreover, conditioned medium of hSCs that were cultivated on Perimaix was able to modify neurite outgrowth from sensory dorsal root ganglion neurons. Overall these data indicate that Perimaix is able to provide a matrix that can promote the attachment and supports process extension, migration, and proliferation of hSC. Sabien G. A. van Neerven, Laura Krings, Kirsten Haastert-Talini, Michael Vogt, René H. Tolba, Gary Brook, Norbert Pallua, and Ahmet Bozkurt Copyright © 2014 Sabien G. A. van Neerven et al. All rights reserved. Association between Oxidative Stress and Outcome in Different Subtypes of Acute Ischemic Stroke Thu, 08 May 2014 09:28:42 +0000 Objectives. This study investigated serum thiobarbituric acid-reactive substances (TBARS) and free thiol levels in different subtypes of acute ischemic stroke (AIS) and evaluated their association with clinical outcomes. Methods. This prospective study evaluated 100 AIS patients, including 75 with small-vessel and 25 with large-vessel diseases. Serum oxidative stress (TBARS) and antioxidant (thiol) were determined within 48 hours and days 7 and 30 after stroke. For comparison, 80 age- and sex-matched participants were evaluated as controls. Results. Serum TBARS was significantly higher and free thiol was lower in stroke patients than in the controls on days 1 and 7 after AIS. The level of free thiol was significantly lower in the large-vessel disease than in the small-vessel disease on day 7 after stroke. Using the stepwise logistic regression model for potential variables, only stroke subtype, NIHSS score, and serum TBARS level were independently associated with three-month outcome. Higher TBARS and lower thiol levels in the acute phase of stroke were associated with poor outcome. Conclusions. Patients with large-vessel disease have higher oxidative stress but lower antioxidant defense compared to those with small-vessel disease after AIS. Serum TBARS level at the acute phase of stroke is a potential predictor for three-month outcome. Nai-Wen Tsai, Ya-Ting Chang, Chi-Ren Huang, Yu-Jun Lin, Wei-Che Lin, Ben-Chung Cheng, Chih-Min Su, Yi-Fang Chiang, Shu-Fang Chen, Chih-Cheng Huang, Wen-Neng Chang, and Cheng-Hsien Lu Copyright © 2014 Nai-Wen Tsai et al. All rights reserved. Salvage Radiosurgery for Selected Patients with Recurrent Malignant Gliomas Wed, 07 May 2014 11:14:43 +0000 Purpose. To analyse the survival after salvage radiosurgery and to identify prognostic factors. Methods. We retrospectively reviewed 87 consecutive patients, with recurrent high-grade glioma, that underwent stereotactic radiosurgery between 1997 and 2010. We evaluated the survival after initial diagnosis and after reirradiation. The prognostic factors were analysed by bivariate and multivariate Cox regression model. Results. The median age was 48 years old. The primary histology included anaplastic astrocytoma (47%) and glioblastoma (53%). A margin dose of 18 Gy was administered in the majority of cases (74%). The median survival after initial diagnosis was 21 months (39 months for anaplastic astrocytoma and 18.5 months for glioblastoma) and after reirradiation it was 10 months (17 months for anaplastic astrocytoma and 7.5 months for glioblastoma). In the bivariate analyses, the prognostic factors significantly associated with survival after reirradiation were age, tumour and treatment volume at recurrence, recursive partitioning analyses classification, Karnofsky performance score, histology, and margin to the planning target volume. Only the last four showed significant association in the multivariate analyses. Conclusion. stereotactic radiosurgery is a safe and may be an effective treatment option for selected patients diagnosed with recurrent high-grade glioma. The identified prognostic factors could help individualise the treatment. Miguel Martínez-Carrillo, Isabel Tovar-Martín, Mercedes Zurita-Herrera, Rosario Del Moral-Ávila, Rosario Guerrero-Tejada, Enrique Saura-Rojas, Juan Luis Osorio-Ceballos, Juan Pedro Arrebola-Moreno, and José Expósito-Hernández Copyright © 2014 Miguel Martínez-Carrillo et al. All rights reserved. IDH1R132H Mutation Increases U87 Glioma Cell Sensitivity to Radiation Therapy in Hypoxia Wed, 07 May 2014 06:44:31 +0000 Objective. IDH1 codon 132 mutation (mostly Arg132His) is frequently found in gliomas and is associated with longer survival. However, it is still unclear whether IDH1 mutation renders the cell more vulnerable to current treatment, radio- and chemotherapy. Materials and Methods. We transduced U87 with wild type IDH1 or expressing lentivirus and analyzed the radiosensitivity (dose ranging 0 to 10 Gy) under normoxia (20% O2) and moderate hypoxia (1% O2). Results. We observed that U87 cells grow faster in hypoxia and were more sensitive to radiotherapy (in terms of cell mortality and colony formation assay) compared to nontransduced U87 and IDH1wt cells. This effect was not observed in normoxia. Conclusion. These data suggest that mutation increases radiosensitivity in mild hypoxic conditions. Xiao-Wei Wang, Marianne Labussière, Samuel Valable, Elodie A. Pérès, Jean-Sébastien Guillamo, Myriam Bernaudin, and Marc Sanson Copyright © 2014 Xiao-Wei Wang et al. All rights reserved. The Inhibitory Effect of Somatostatin Receptor Activation on Bee Venom-Evoked Nociceptive Behavior and pCREB Expression in Rats Wed, 07 May 2014 00:00:00 +0000 The present study examined nociceptive behaviors and the expression of phosphorylated cAMP response element-binding protein (pCREB) in the dorsal horn of the lumbar spinal cord and the dorsal root ganglion (DRG) evoked by bee venom (BV). The effect of intraplantar preapplication of the somatostatin analog octreotide on nociceptive behaviors and pCREB expression was also examined. Subcutaneous injection of BV into the rat unilateral hindpaw pad induced significant spontaneous nociceptive behaviors, primary mechanical allodynia, primary thermal hyperalgesia, and mirror-thermal hyperalgesia, as well as an increase in pCREB expression in the lumbar spinal dorsal horn and DRG. Octreotide pretreatment significantly attenuated the BV-induced lifting/licking response and mechanical allodynia. Local injection of octreotide also significantly reduced pCREB expression in the lumbar spinal dorsal horn and DRG. Furthermore, pretreatment with cyclosomatostatin, a somatostatin receptor antagonist, reversed the octreotide-induced inhibition of the lifting/licking response, mechanical allodynia, and the expression of pCREB. These results suggest that BV can induce nociceptive responses and somatostatin receptors are involved in mediating the antinociception, which provides new evidence for peripheral analgesic action of somatostatin in an inflammatory pain state. Li Li, Rong Luo, Yuan Guo, Fanrong Yao, Dongyuan Cao, Shaojie Ma, Jun Wang, Huisheng Wang, and Yan Zhao Copyright © 2014 Li Li et al. All rights reserved. Elevated Serum Vascular Cell Adhesion Molecule-1 Is Associated with Septic Encephalopathy in Adult Community-Onset Severe Sepsis Patients Tue, 06 May 2014 07:25:16 +0000 Background and Aim. Septic encephalopathy (SE) is a common complication of severe sepsis. Increased concentrations of circulating soluble adhesion molecules are reported in septic patients. This study aimed to determine whether serum adhesion molecules are associated with SE. Methods. Seventy nontraumatic, nonsurgical adult patients with severe sepsis admitted through ER were evaluated. Serum adhesion molecules were assessed for their relationship with SE, and compared with other clinical predictors and biomarkers. Results. Twenty-three (32.8%) patients had SE. SE group had higher in-hospital mortality (40% versus 11%, ) and their sVCAM-1, sICAM-1, and lactate levels on admission were also higher than non-SE group. By stepwise logistic regression model, sVCAM-1, age, and maximum 24-hours SOFA score were independently associated with septic encephalopathy. The AUC analysis of ROC curve of different biomarkers showed that sVCAM-1 is better to predict SE. The sVCAM-1 levels in the SE group were significantly higher than those of the non-SE group at three time periods (Days 1, 4, and 7). Conclusions. Septic encephalopathy implies higher mortality in nontraumatic, nonsurgical patients with severe sepsis. VCAM-1 level on presentation is a more powerful predictor of SE in these patients than lactate concentration and other adhesion molecules on admission. Chih-Min Su, Hsien-Hung Cheng, Tsung-Cheng Tsai, Sheng-Yuan Hsiao, Nai-Wen Tsai, Wen-Neng Chang, Wei-Che Lin, Ben-Chung Cheng, Yu-Jih Su, Ya-Ting Chang, Yi-Fang Chiang, Chia-Te Kung, and Cheng-Hsien Lu Copyright © 2014 Chih-Min Su et al. All rights reserved. Activity and Safety of Bevacizumab Plus Fotemustine for Recurrent Malignant Gliomas Sun, 04 May 2014 00:00:00 +0000 Background. No established chemotherapeutic regimen exists for the treatment of recurrent malignant gliomas (rMGs). Herein, we report the activity and safety results of the bevacizumab (B) plus fotemustine (FTM) combination for the treatment of rMGs. Patients and Methods. An induction phase consisted of B 10 mg/kg days 1, 15 plus FTM 65 mg/m2 days 1, 8, and 15. Nonprogressive patients entered the maintenance phase with B 10 mg/kg plus FTM 75 mg/m2 every 3 weeks. The primary endpoint was response rate; secondary endpoints included safety, progression free survival (PFS), and overall survival (OS). Results. Twenty-six patients affected by recurrent MGs (50% glioblastoma) were enrolled. Eight partial responses (31%) were observed. Median PFS and OS were 4 (95% C.I.: 2.8–5.1) and 6 months (95% C.I.: 4.2–7.8), respectively. Responses were significantly associated with both improved PFS and OS ( and , resp.). Treatment adverse events were mostly mild to moderate in intensity. Bevacizumab-related adverse events included grade 3 venous thromboembolic event (8%), grade 2 epistaxis (4%), hypertension (8%), and gastrointestinal perforation (4%). Conclusions. Bevacizumab plus FTM showed activity and good tolerability in pretreated MGs. Further investigations are needed in order to verify the benefits deriving from the addition of B to a cytotoxic in this clinical setting of patients. V. Vaccaro, A. Fabi, A. Vidiri, D. Giannarelli, G. Metro, S. Telera, S. Vari, F. Piludu, M. A. Carosi, V. Villani, F. Cognetti, A. Pompili, L. Marucci, C. M. Carapella, and A. Pace Copyright © 2014 V. Vaccaro et al. All rights reserved. IDH Mutations: Genotype-Phenotype Correlation and Prognostic Impact Wed, 30 Apr 2014 13:38:07 +0000 IDH1/2 mutation is the most frequent genomic alteration found in gliomas, affecting 40% of these tumors and is one of the earliest alterations occurring in gliomagenesis. We investigated a series of 1305 gliomas and showed that IDH mutation is almost constant in 1p19q codeleted tumors. We found that the distribution of IDH1R132H, IDH1nonR132H, and IDH2 mutations differed between astrocytic, mixed, and oligodendroglial tumors, with an overrepresentation of IDH2 mutations in oligodendroglial phenotype and an overrepresentation of IDH1nonR132H in astrocytic tumors. We stratified grade II and grade III gliomas according to the codeletion of 1p19q and IDH mutation to define three distinct prognostic subgroups: 1p19q and IDH mutated, IDH mutated—which contains mostly TP53 mutated tumors, and none of these alterations. We confirmed that IDH mutation with a hazard ratio = 0.358 is an independent prognostic factor of good outcome. These data refine current knowledge on IDH mutation prognostic impact and genotype-phenotype associations. Xiao-Wei Wang, Pietro Ciccarino, Marta Rossetto, Blandine Boisselier, Yannick Marie, Virginie Desestret, Vincent Gleize, Karima Mokhtari, Marc Sanson, and Marianne Labussière Copyright © 2014 Xiao-Wei Wang et al. All rights reserved. Association between Autoimmune Rheumatic Diseases and the Risk of Dementia Wed, 30 Apr 2014 12:42:51 +0000 Aim. Autoimmune rheumatic diseases (ARD) are characterized by systemic inflammation and may affect multiple organs and cause vascular events such as ischemic stroke and acute myocardial infarction. However, the association between ARD and increased risk of dementia is uncertain. This is a retrospective cohort study to investigate and compare the risk of dementia between patients clinically diagnosed with ARD and non-ARD patients during a 5-year follow-up period. Methods. Data were obtained from the Longitudinal Health Insurance Database 2000 (LHID2000). We included 1221 patients receiving ambulatory or hospitalization care and 6105 non-ARD patients; patients were matched by sex, age, and the year of index use of health care. Each patient was studied for 5 years to identify the subsequent manifestation of dementia. The data obtained were analyzed by Cox proportional hazard regression. Results. During the 5-year follow-up period, 30 ARD (2.48%) and 141 non-ARD patients (2.31%) developed dementia. During the 5-year follow-up period, there were no significant differences in the risks of any type of dementia (adjusted hazard ratio (HR), 1.18; 95% CI, 0.79–1.76) in the ARD group after adjusting for demographics and comorbidities. Conclusions. Within the 5-year period, patients with and without ARD were found to have similar risks of developing dementia. Kang Lu, Hao-Kuang Wang, Chih-Ching Yeh, Chih-Yuan Huang, Pi-Shan Sung, Liang-Chao Wang, Chih-Hsin Muo, Fung-Chang Sung, Han-Jung Chen, Ying-Chun Li, Li-Ching Chang, and Kuen-Jer Tsai Copyright © 2014 Kang Lu et al. All rights reserved. Predictors of Memory and Processing Speed Dysfunctions after Traumatic Brain Injury Tue, 29 Apr 2014 11:55:00 +0000 Background. The aims of this study were to evaluate the predictive value of admission Glasgow Coma Scale (GCS) scores, duration of unconsciousness, neurosurgical intervention, and countercoup lesion on the impairment of memory and processing speed functions six months after a traumatic brain injury (TBI) based on a structural equation modeling. Methods. Thirty TBI patients recruited from Neurosurgical Department at the Kaohsiung Medical University Hospital were administered the Wechsler Memory Scale-III (WMS-III) and the Wechsler Adult Intelligence Scale-III processing speed index to evaluate the memory and processing speed functions. Results. The study showed that GCS scores accounted for 40% of the variance in memory/processing speed. No significant predictive effects were found for the other three variables. GCS classification at the time of TBI seems to correspond moderately to the severity of memory/processing speed dysfunctions. Conclusions. The present study demonstrated that admission GCS score is a robust predictor of memory/processing speed dysfunctions after TBI. The results should be replicated with a large sample of patients with TBI, or be extended by examining other potential clinical predictors. William Winardi, Aij-Lie Kwan, Tse-Lun Wang, Yu-Feng Su, Chun-Po Yen, Hung-Pei Tsai, Jason Sheehan, and Chwen-Yng Su Copyright © 2014 William Winardi et al. All rights reserved. Nerve Injury-Induced c-Jun Activation in Schwann Cells Is JNK Independent Mon, 28 Apr 2014 09:55:33 +0000 We investigated (a) if activation of the mitogen activated protein kinase (MAPK) pathway was linked to the stress activated protein kinase (SAPK) pathway and (b) if JNK was required for activation of c-Jun in Schwann cells of rat sciatic nerve following injury. To this aim, ERK1/2 and the transcription factors c-Jun and ATF-3 were studied by immunohistochemistry in segments of transected nerves. We utilized pharmacological inhibitors of both signal transduction pathways in vitro to determine the effects on downstream signalling events, such as c-Jun activation, and on Schwann cell survival and proliferation. A transection induces c-Jun and ATF-3 transcription in Schwann cells. These events are followed by Schwann cell activation of c-Jun in the injured nerve. The MAPK inhibitor U0126 blocked ERK1/2 activation and reduced Schwann cell proliferation as well as induction of c-Jun transcription. The JNK inhibitor SP600125 reduced Schwann cell proliferation, but did not affect the expression of ERK1/2 or injury-induced increases in c-Jun or ATF-3 levels. Importantly, nerve injury induces Schwann cell activation of c-Jun by phosphorylation, which, in contrast to in sensory neurons, is JNK independent. MAP kinases, other than JNK, can potentially activate c-Jun in Schwann cells following injury; information that is crucial to create new nerve reconstruction strategies. Charlotta Lindwall Blom, Lisa B. Mårtensson, and Lars B. Dahlin Copyright © 2014 Charlotta Lindwall Blom et al. All rights reserved. BMPs as Therapeutic Targets and Biomarkers in Astrocytic Glioma Mon, 28 Apr 2014 07:36:01 +0000 Astrocytic glioma is the most common brain tumor. The glioma initiating cell (GIC) fraction of the tumor is considered as highly chemoresistant, suggesting that GICs are responsible for glioma relapse. A potential treatment for glioma is to induce differentiation of GICs to a more benign and/or druggable cell type. Given BMPs are among the most potent inducers of GIC differentiation, they have been considered as noncytotoxic therapeutic compounds that may be of use to prevent growth and recurrence of glioma. We herein summarize advances made in the understanding of the role of BMP signaling in astrocytic glioma, with a particular emphasis on the effects exerted on GICs. We discuss the prognostic value of BMP signaling components and the implications of BMPs in the differentiation of GICs and in their sensitization to alkylating drugs and oncolytic therapy/chemotherapy. This mechanistic insight may provide new opportunities for therapeutic intervention of brain cancer. Pilar González-Gómez, Nilson Praia Anselmo, and Helena Mira Copyright © 2014 Pilar González-Gómez et al. All rights reserved. The Association among Antioxidant Enzymes, Autoantibodies, and Disease Severity Score in Systemic Lupus Erythematosus: Comparison of Neuropsychiatric and Nonneuropsychiatric Groups Sun, 27 Apr 2014 13:53:33 +0000 Background. Antioxidative capacity plays an important role in the severity of systemic lupus erythematosus (SLE), which is characterized by autoantibodies. This study aimed to determine the relationship among autoantibody titers, antioxidative stress reserve, and severity of SLE. Methods. The autoantibody titers, clinical markers, antioxidant enzyme levels, and disease activity index (SLEDAI-2k) of 32 SLE patients and 16 healthy controls were compared. We also compared both the neuropsychiatric (NPSLE) and nonneuropsychiatric (non-NPSLE) groups. Results. Superoxide dismutase in red blood cells was significantly lower in the SLE than in the control group. CRP levels are significant higher in SLE patients than in control group (). Among the autoantibodies, anti-U1RNP , a-Sm , and anti-ribosomal p significantly negatively correlated with glutathione levels. There has no significant correlation between SLE disease activity indexes (SLEDAI) and levels of C3, C4, and antioxidant enzymes. Conclusions. Erythrocyte superoxide dismutase is significantly lower in both NPSLE and non-NPSLE groups. SLE patients have both higher CRP and autoantibodies level and decreased superoxide dismutase level than the healthy control group. Yu-Jih Su, Tien-Tsai Cheng, Chung-Jen Chen, Wen-Chan Chiu, Wen-Neng Chang, Nai-Wen Tsai, Chia-Te Kung, Wei-Che Lin, Chih-Cheng Huang, Ya-Ting Chang, Chih-Min Su, Yi-Fang Chiang, Ben-Chung Cheng, and Cheng-Hsien Lu Copyright © 2014 Yu-Jih Su et al. All rights reserved. Differential Hypermethylation of Death-Associated Protein Kinase Promoter in Central Neurocytoma and Oligodendroglioma Sun, 27 Apr 2014 13:09:37 +0000 Background. Central neurocytoma and oligodendroglioma are rare tumors of the central nervous system. However, diagnosis between these two types of tumors is challenging due to their many cytological and histological similarities. Death-associated protein kinase (DAPK) is a calcium/calmodulin-regulated serine/threonine protein kinase involved in many apoptosis pathways, and repressed expression of DAPK by promoter hypermethylation has been found in a variety of human cancers. The purpose of this study was to assess DAPK protein expression and promoter hypermethylation in central neurocytoma and oligodendroglioma. Method. Central neurocytoma and oligodendroglioma samples were obtained from age- and sex-matched patients. DAPK protein expression was performed using immunohistochemical assays in formalin-fixed, paraffin-embedded sections. DAPK promoter hypermethylation was carried out using bisulfite-modified genomic DNA in methylation-specific PCR followed by separation in agarose gels. Findings. A statistically significant difference () in DAPK promoter hypermethylation between central neurocytoma (76.9%) and oligodendroglioma (20%) was observed. High levels of DAPK protein expression were generally found in oligodendroglioma (90%), compared with 38.5% in central neurocytoma (; not statistically significant). There was an inverse correlation between DAPK protein expression and DAPK promoter hypermethylation in the cohort of 23 patients (). Conclusions. The results show that DAPK promoter hypermethylation and repressed expression of DAPK protein were more common in central neurocytoma than in oligodendroglioma. Thus, DAPK promoter hypermethylation could be useful for differential diagnosis between these two types of tumors, whereas DAPK protein expression might be less predictive. The role of DAPK promoter hypermethylation in the pathogenesis of central neurocytoma warrants further study. Chia-Li Chung, Hung Pei Tsai, Cheng-Yu Tsai, Wan-Tzu Chen, Ann-Shung Lieu, Chih-Jen Wang, Jason Sheehan, Chee-Yin Chai, and Aij-Lie Kwan Copyright © 2014 Chia-Li Chung et al. All rights reserved. Inflammatory Profiling of Schwann Cells in Contact with Growing Axons Distal to Nerve Injury Sun, 27 Apr 2014 08:03:50 +0000 Activated Schwann cells distal to nerve injury upregulate inflammatory mediators, including cytokines. The goal of the present study was to investigate expression of proinflammatory (IL-1β, TNFα) and anti-inflammatory cytokines (IL-4, IL-10) in activated Schwann cells in relation to growing axons distal to crush injury of rat sciatic nerves. Seven days from sciatic nerve crush, transverse cryostat sections were cut 5 mm distal to lesion and incubated for double immunostaining to indicate Schwann cells (GFAP or S100b) and individual investigated cytokines or to demonstrate growing axons (GAP43). The Schwann cells of naïve sciatic nerves and those removed from sham-operated rats displayed similar weak immunoreactivity for the investigated cytokines. In contrast, increased intensity of cytokine immunofluorescence was found in Schwann cells distal to crush lesion. The cytokine-positive Schwann cells were found in close contact with growing axons detected by immunostaining for GAP43. The results of immunohistochemical analysis distal to nerve crush injury suggest that inflammatory profiling of Schwann cells including upregulation of both pro- and anti-inflammatory cytokines does not prevent growth of axons distal to nerve crush injury. Petr Dubový, Ilona Klusáková, and Ivana Hradilová Svíženská Copyright © 2014 Petr Dubový et al. All rights reserved. Tumor and Endothelial Cell Hybrids Participate in Glioblastoma Vasculature Thu, 24 Apr 2014 12:57:01 +0000 Background. Recently antiangiogenic therapy with bevacizumab has shown a high but transient efficacy in glioblastoma (GBM). Indeed, GBM is one of the most angiogenic human tumors and endothelial proliferation is a hallmark of the disease. We therefore hypothesized that tumor cells may participate in endothelial proliferation of GBM. Materials and Methods. We used EGFR FISH Probe to detect EGFR amplification and anti-CD31, CD105, VE-cadherin, and vWF to identify endothelial cells. Endothelial and GBM cells were grown separately, labeled with GFP and DsRed lentiviruses, and then cocultured with or without contact. Results. In a subset of GBM tissues, we found that several tumor endothelial cells carry EGFR amplification, characteristic of GBM tumor cells. This observation was reproduced in vitro: when tumor stem cells derived from GBM were grown in the presence of human endothelial cells, a fraction of them acquired endothelial markers (CD31, CD105, VE-cadherin, and vWF). By transduction with GFP and DsRed expressing lentiviral vectors, we demonstrate that this phenomenon is due to cell fusion and not transdifferentiation. Conclusion. A fraction of GBM stem cells thus has the capacity to fuse with endothelial cells and the resulting hybrids may participate in tumor microvascular proliferation and in treatment resistance. Soufiane El Hallani, Carole Colin, Younas El Houfi, Ahmed Idbaih, Blandine Boisselier, Yannick Marie, Philippe Ravassard, Marianne Labussière, Karima Mokhtari, Jean-Léon Thomas, Jean-Yves Delattre, Anne Eichmann, and Marc Sanson Copyright © 2014 Soufiane El Hallani et al. All rights reserved. The Association between Autoantibodies and Peripheral Neuropathy in Lupus Nephritis Thu, 24 Apr 2014 09:12:22 +0000 Background and Aim. The sensitivity and specificity of biomarkers used for predicting peripheral neuropathy in patients with systemic lupus erythematosus (SLE) and nephritis (SLE-LN) remain unsatisfactory. This study aimed to determine the autoantibodies levels in SLE-LN patients with peripheral neuropathy. Methods. Data of 559 SLE-LN patients were collected retrospectively, including titers of autoantibodies, electrodiagnostic studies, and clinical manifestations. Results. The neurologic manifestations of the SLE-LN patients were diverse and nonspecific. The prevalence rate of peripheral polyneuropathy was 2.68%, of which about 73.33% was mixed sensory-motor polyneuropathy. Numbness and functional gastrointestinal problems were the most prevalent symptoms and these were noted in every subtype of peripheral neuropathy. Among all the serology markers, anti-Ro was significantly associated with neuropathy related to SLE (). Conclusion. Peripheral neuropathy among LN patients is rare and may be easily overlooked. This study demonstrated that positive anti-Ro antibody may imply neuropathy in LN patients. Thus, anti-Ro can be considered a biomarker that should be added to the panel of conventional autoantibodies in LN patients. Yu-Jih Su, Chi-Ren Huang, Wen-Neng Chang, Nai-Wen Tsai, Chia-Te Kung, Wei-Che Lin, Chih-Cheng Huang, Chih-Min Su, Ben-Chung Cheng, Ya-Ting Chang, and Cheng-Hsien Lu Copyright © 2014 Yu-Jih Su et al. All rights reserved. Kinematic Metrics Based on the Virtual Reality System Toyra as an Assessment of the Upper Limb Rehabilitation in People with Spinal Cord Injury Wed, 23 Apr 2014 09:27:05 +0000 The aim of this study was to develop new strategies based on virtual reality that can provide additional information to clinicians for the rehabilitation assessment. Virtual reality system Toyra has been used to record kinematic information of 15 patients with cervical spinal cord injury (SCI) while performing evaluation sessions using the mentioned system. Positive correlation, with a moderate and very strong association, has been found between clinical scales and kinematic data, considering only the subscales more closely related to the upper limb function. A set of metrics was defined combining these kinematic data to obtain parameters of reaching amplitude, joint amplitude, agility, accuracy, and repeatability during the evaluation sessions of the virtual reality system Toyra. Strong and moderate correlations have been also found between the metrics reaching and joint amplitude and the clinical scales. Fernando Trincado-Alonso, Iris Dimbwadyo-Terrer, Ana de los Reyes-Guzmán, Patricia López-Monteagudo, Alberto Bernal-Sahún, and Ángel Gil-Agudo Copyright © 2014 Fernando Trincado-Alonso et al. All rights reserved. Treatment of Malignant Gliomas in Elderly Patients: A Concise Overview of the Literature Tue, 22 Apr 2014 13:35:04 +0000 Gliomas are the most frequent primary brain tumors and the incidence data has increased in the elderly population. Unfortunately, prospective studies on this population are few and so the right treatment is unknown. In the elderly patients no standard treatment has been established and therefore the optimal treatment should be individualized. We performed a review analyzing the prognostic and predictive factors, the clinical studies, and the correct management of this population. Patrizia Farina, Giuseppe Lombardi, Eleonora Bergo, Anna Roma, and Vittorina Zagonel Copyright © 2014 Patrizia Farina et al. All rights reserved. Serial Serum Leukocyte Apoptosis Levels as Predictors of Outcome in Acute Traumatic Brain Injury Thu, 17 Apr 2014 13:33:18 +0000 Background. Apoptosis associates with secondary brain injury after traumatic brain injury (TBI). This study posits that serum leukocyte apoptosis levels in acute TBI are predictive of outcome. Methods. Two hundred and twenty-nine blood samples from 88 patients after acute TBI were obtained on admission and on Days 4 and 7. Serial apoptosis levels of different leukocyte subsets were examined in 88 TBI patients and 27 control subjects. Results. The leukocyte apoptosis was significantly higher in TBI patients than in controls. Brief unconsciousness (), motor deficits (), GCS (), ISS (), WBC count (), late apoptosis in lymphocytes and monocytes on Day 1 ( and , resp.), subdural hemorrhage on initial brain CT (), neurosurgical intervention (), and acute posttraumatic seizure () were significant risk factors of outcome. Only motor deficits () and late apoptosis in monocytes on Day 1 () were independently associated with outcome. A cutoff value of 5.72% of late apoptosis in monocytes was associated with poor outcome in acute TBI patients. Conclusion. There are varying degrees of apoptosis in patients following TBI and in healthy individuals. Such differential expression suggests that apoptosis in different leukocyte subsets plays an important role in outcome following injury. Hung-Chen Wang, Tzu-Ming Yang, Yu-Jun Lin, Wu-Fu Chen, Jih-Tsun Ho, Yu-Tsai Lin, Aij-Lie Kwan, and Cheng-Hsien Lu Copyright © 2014 Hung-Chen Wang et al. All rights reserved. The Multiple Silicone Tube Device, “Tubes within a Tube,” for Multiplication in Nerve Reconstruction Thu, 17 Apr 2014 07:05:51 +0000 Multiple nerve branches were created during the regeneration procedure after a nerve injury and such multiple branches are suggested to be used to control, for example, prosthesis with many degrees of freedom. Transected rat sciatic nerve stumps were inserted into a nine mm long silicone tube, which contained four, five mm long, smaller tubes, thus leaving a five mm gap for regenerating nerve fibers. Six weeks later, several new nerve structures were formed not only in the four smaller tubes, but also in the spaces in-between. The 7–9 new continuous nerve structures, which were isolated as individual free nerves after removal of the tubes, were delineated by a perineurium and contained both myelinated and unmyelinated nerve fibers as well as blood vessels. Stimulation of the proximal nerve elicited contractions in distal muscles. Thin metal electrodes, inserted initially into the smaller tubes in some experiments, became embedded in the new nerve structures and when stimulated contractions of the distal muscles were observed. The “tubes within a tube” technique, creating multiple new nerves from a single “mother” nerve, can be used to record multiple signals for prosthetic device control or as sources for supply of multiple denervated targets. Fredrik Johansson and Lars B. Dahlin Copyright © 2014 Fredrik Johansson and Lars B. Dahlin. All rights reserved. Ghostman: Augmented Reality Application for Telerehabilitation and Remote Instruction of a Novel Motor Skill Tue, 15 Apr 2014 14:00:33 +0000 This paper describes a pilot study using a prototype telerehabilitation system (Ghostman). Ghostman is a visual augmentation system designed to allow a physical therapist and patient to inhabit each other’s viewpoint in an augmented real-world environment. This allows the therapist to deliver instruction remotely and observe performance of a motor skill through the patient’s point of view. In a pilot study, we investigated the efficacy of Ghostman by using it to teach participants to use chopsticks. Participants were randomized to a single training session, receiving either Ghostman or face-to-face instructions by the same skilled instructor. Learning was assessed by measuring retention of skills at 24-hour and 7-day post instruction. As hypothesised, there were no differences in reduction of error or time to completion between participants using Ghostman compared to those receiving face-to-face instruction. These initial results in a healthy population are promising and demonstrate the potential application of this technology to patients requiring learning or relearning of motor skills as may be required following a stroke or brain injury. Winyu Chinthammit, Troy Merritt, Scott Pedersen, Andrew Williams, Denis Visentin, Robert Rowe, and Thomas Furness Copyright © 2014 Winyu Chinthammit et al. All rights reserved. Sex Differences of Uncinate Fasciculus Structural Connectivity in Individuals with Conduct Disorder Mon, 14 Apr 2014 12:17:18 +0000 Conduct disorder (CD) is one of the most common behavior disorders in adolescents, such as impulsivity, aggression, and running from school. Males are more likely to develop CD than females, and two previous diffusion tensor imaging (DTI) studies have demonstrated abnormal microstructural integrity in the uncinate fasciculus (UF) in boys with CD compared to a healthy control group. However, little is known about changes in the UF in females with CD. In this study, the UF was illustrated by tractography; then, the fractional anisotropy (FA), axial diffusivity, mean diffusion, radial diffusivity (RD), and the length and number of the UF fiber bundles were compared between male and female patients with CD and between female patients with CD and female healthy controls, as well as between males with CD and healthy males. We found that males with CD showed significantly higher FA of the bilateral UF and significantly lower RD of the left UF when comparing with females with CD. Meanwhile, significantly higher FA and lower RD of the bilateral UF were also found in boys with CD relative to the male healthy controls. Our results replicated previous reports that the microstructural integrity of the UF was abnormal in boys with CD. Additionally, our results demonstrated significant gender effects on the UF of patients with CD, which may indicate why boys have higher rates of conduct problems than girls. Jibiao Zhang, Junling Gao, Huqing Shi, Bingsheng Huang, Xiang Wang, Weijun Situ, Weixiong Cai, Jinyao Yi, Xiongzhao Zhu, and Shuqiao Yao Copyright © 2014 Jibiao Zhang et al. All rights reserved. The Association between Serological Biomarkers and Primary Sjogren’s Syndrome Associated with Peripheral Polyneuropathy Sun, 13 Apr 2014 13:20:20 +0000 Background and Aim. The sensitivity and specificity of biomarkers used for predicting peripheral neuropathy of Sjogren’s syndrome (SJS) patients remain unsatisfactory. This study aimed to determine the prognostic value of circulating autoantibodies levels in SJS patients with peripheral neuropathy. Methods. Two hundred and fifty serological positive (either anti-Ro or anti-La positive) SJS patients’ data were collected retrospectively. The titers of autoantibodies, electrophysiology reports, and clinical manifestation were reviewed. Results. The prevalence rate of peripheral neuropathy is 7.2% in our study. Regarding classification of peripheral neuropathy, 12 had mixed sensorimotor polyneuropathy, six had cranial neuropathy. After stepwise logistic regression analysis, anti-β2 glycoprotein I (aβ2GP I) and perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) were significantly associated with peripheral neuropathy in serology positive SJS (, , resp.). Conclusion. The occurrence of peripheral neuropathy among SJS patients is not frequent and easily overlooked. Our study demonstrated that aβ2GP I and p-ANCA levels may imply the danger of the occurrence of neuropathy in SJS patients, and they can be considered a biomarker that should be added to the panel of conventional autoantibody in SJS patients. Che-Wei Hsu, Yu-Jih Su, Wen-Neng Chang, Nai-Wen Tsai, Wen-Chan Chiu, Ben-Chung Cheng, Chih-Min Su, Chi-Ren Huang, Ya-Ting Chang, and Cheng-Hsien Lu Copyright © 2014 Che-Wei Hsu et al. All rights reserved. Immune Responses in Parkinson’s Disease: Interplay between Central and Peripheral Immune Systems Sun, 13 Apr 2014 13:07:40 +0000 The etiology of Parkinson’s disease (PD) is complex and most likely involves numerous environmental and heritable risk factors. Recent studies establish that central and peripheral inflammation occurs in the prodromal stage of the disease and sustains disease progression. Aging, heritable risk factors, or environmental exposures may contribute to the initiation of central or peripheral inflammation. One emerging hypothesis is that inflammation plays a critical role in PD neuropathology. Increasing evidence suggest that activation of the peripheral immune system exacerbates the discordant central inflammatory response and synergistically drives neurodegeneration. We provide an overview of current knowledge on the temporal profile of central and peripheral immune responses in PD and discuss the potential synergistic effects of the central and peripheral inflammation in disease development. The understanding of the nature of the chronic inflammation in disease progression and the possible risk factors that contribute to altered central and peripheral immune responses will offer mechanistic insights into PD etiology and pathology and benefit the development of effective tailored therapeutics for human PD. Xiaomin Su and Howard J. Federoff Copyright © 2014 Xiaomin Su and Howard J. Federoff. All rights reserved. Progesterone and Mental Rotation Task: Is There Any Effect? Thu, 10 Apr 2014 14:10:49 +0000 Mental rotation task (MRT) incorporates elements of spatial abilities, important in many professions, with people of both genders involved. Importantly, these are the areas where spatial tasks might be performed for long time periods; thus adverse effects of mental fatigue are highly unwanted. Substantial variation of MRT performance in relation to estrogen levels has been observed in many studies, whereas the role of progesterone remains elusive. Here we aimed to elucidate the effect of progesterone level on the long-duration (1.5 hours) performance of MRT. We included three groups of subjects: a group of males as a control, a group of females in their follicular phase (low progesterone) and a group of females in their luteal phase (high progesterone), MRT accuracy and response time, subjective fatigue ratings and cardiovascular measures together with 17β-estradiol and progesterone concentrations were analyzed. We found that subjective ratings of fatigue increased, performance accuracy increased, and mean response times decreased during the task in all groups. Females in luteal phase were significantly slower not only than men, but also than females in their follicular phase. An increase in subjective fatigue ratings was positively related to progesterone level—at higher progesterone levels, females felt more tired. Donatas Noreika, Inga Griškova-Bulanova, Aidas Alaburda, Mindaugas Baranauskas, and Ramunė Grikšienė Copyright © 2014 Donatas Noreika et al. All rights reserved. The Combination of Carmustine Wafers and Fotemustine in Recurrent Glioblastoma Patients: A Monoinstitutional Experience Wed, 09 Apr 2014 14:01:34 +0000 Background. To date, there is no standard treatment for recurrent glioblastoma. We analyzed the feasibility of second surgery plus carmustine wafers followed by intravenous fotemustine. Methods. Retrospectively, we analyzed patients with recurrent glioblastoma treated with this multimodal strategy. Results. Twenty-four patients were analyzed. The median age was 53.6; all patients had KPS between 90 and 100; 19 patients (79%) performed a gross total resection > 98% and 5 (21%) a gross total resection > 90%. The median progression-free survival from second surgery was 6 months (95% CI 3.9–8.05) and the median OS was 14 months (95% CI 11.1–16.8 months). Toxicity was predominantly haematological: 5 patients (21%) experienced grade 3-4 thrombocytopenia and 3 patients (12%) grade 3-4 leukopenia. Conclusion. This multimodal strategy may be feasible in patients with recurrent glioblastoma, in particular, for patients in good clinical conditions. Giuseppe Lombardi, Alessandro Della Puppa, Fable Zustovich, Ardi Pambuku, Patrizia Farina, Pasquale Fiduccia, Anna Roma, and Vittorina Zagonel Copyright © 2014 Giuseppe Lombardi et al. All rights reserved. Microparticles: A New Perspective in Central Nervous System Disorders Wed, 09 Apr 2014 13:53:32 +0000 Microparticles (MPs) are a heterogeneous population of small cell-derived vesicles, ranging in size from 0.1 to 1 μm. They contain a variety of bioactive molecules, including proteins, biolipids, and nucleic acids, which can be transferred between cells without direct cell-to-cell contact. Consequently, MPs represent a novel form of intercellular communication, which could play a role in both physiological and pathological processes. Growing evidence indicates that circulating MPs contribute to the development of cancer, inflammation, and autoimmune and cardiovascular diseases. Most cell types of the central nervous system (CNS) have also been shown to release MPs, which could be important for neurodevelopment, CNS maintenance, and pathologies. In disease, levels of certain MPs appear elevated; therefore, they may serve as biomarkers allowing for the development of new diagnostic tools for detecting the early stages of CNS pathologies. Quantification and characterization of MPs could also provide useful information for making decisions on treatment options and for monitoring success of therapies, particularly for such difficult-to-treat diseases as cerebral malaria, multiple sclerosis, and Alzheimer’s disease. Overall, studies on MPs in the CNS represent a novel area of research, which promises to expand the knowledge on the mechanisms governing some of the physiological and pathophysiological processes of the CNS. Stephanie M. Schindler, Jonathan P. Little, and Andis Klegeris Copyright © 2014 Stephanie M. Schindler et al. All rights reserved. 5-Aminolevulinic Acid Fluorescence in High Grade Glioma Surgery: Surgical Outcome, Intraoperative Findings, and Fluorescence Patterns Tue, 08 Apr 2014 00:00:00 +0000 Background. 5-Aminolevulinic acid (5-ALA) fluorescence is a validated technique for resection of high grade gliomas (HGG); the aim of this study was to evaluate the surgical outcome and the intraoperative findings in a consecutive series of patients. Methods. Clinical and surgical data from patients affected by HGG who underwent surgery guided by 5-ALA fluorescence at our Department between June 2011 and February 2014 were retrospectively evaluated. Surgical outcome was evaluated by assessing the resection rate as gross total resection % and %. We finally stratified data for recurrent surgery, tumor location, tumor size, and tumor grade (IV versus III grade sec. WHO). Results. 94 patients were finally enrolled. Overall % and % was achieved in 93% and 100% of patients. Extent of resection was dependent on tumor location, tumor grade , and tumor size . In 43% of patients the boundaries of fluorescent tissue exceeded those of tumoral tissue detected by neuronavigation, more frequently in larger (57%) and recurrent (60%) tumors. Conclusions. 5-ALA fluorescence in HGG surgery enables a GTR in 100% of cases even if selection of patients remains a main bias. Recurrent surgery, and location, size, and tumor grade can predict both the surgical outcome and the intraoperative findings. Alessandro Della Puppa, Pietro Ciccarino, Giuseppe Lombardi, Giuseppe Rolma, Diego Cecchin, and Marta Rossetto Copyright © 2014 Alessandro Della Puppa et al. All rights reserved. Pu-Erh Tea Extract Induces the Degradation of FET Family Proteins Involved in the Pathogenesis of Amyotrophic Lateral Sclerosis Mon, 07 Apr 2014 09:19:09 +0000 FET family proteins consist of fused in sarcoma/translocated in liposarcoma (FUS/TLS), Ewing's sarcoma (EWS), and TATA-binding protein-associated factor 15 (TAF15). Mutations in the copper/zinc superoxide dismutase (SOD1), TAR DNA-binding protein 43 (TDP-43), and FET family proteins are associated with the development of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. There is currently no cure for this disease and few effective treatments are available. Epidemiological studies indicate that the consumption of tea is associated with a reduced risk of developing neurodegenerative diseases. The results of this study revealed that components of a pu-erh tea extract (PTE) interacted with FET family proteins but not with TDP-43 or SOD1. PTE induced the degradation of FET family proteins but had no effects on TDP-43 or SOD1. The most frequently occurring ALS-linked FUS/TLS mutant protein, R521C FUS/TLS, was also degraded in the presence of PTE. Furthermore, ammonium chloride, a lysosome inhibitor, but not lactacystin, a proteasome inhibitor, reduced the degradation of FUS/TLS protein by PTE. PTE significantly reduced the incorporation of R521C FUS/TLS into stress granules under stress conditions. These findings suggest that PTE may have beneficial health effects, including preventing the onset of FET family protein-associated neurodegenerative diseases and delaying the progression of ALS by inhibiting the cytoplasmic aggregation of FET family proteins. Yang Yu, Shuhei Hayashi, Xianbin Cai, Chongye Fang, Wei Shi, Hiroko Tsutsui, and Jun Sheng Copyright © 2014 Yang Yu et al. All rights reserved. CGP 35348, GABAB Receptor Antagonist, Has a Potential to Improve Neuromuscular Coordination and Spatial Learning in Albino Mouse following Neonatal Brain Damage Sun, 06 Apr 2014 13:05:28 +0000 To study the effect of CGP 35348 on learning and memory in albino mice following hypoxia ischemia insult, 10 days old albino mice were subjected to right common carotid artery ligation followed by 8% hypoxia for 25 minutes. Following brain damage, mice were fed on normal rodent diet till they were 13 week old. At this time point, mice were divided into two groups. Group 1 received saline and group 2 intrapertoneally CGP 35348 (1 mg/mL solvent/Kg body weight) for 12 days. A battery of tests used to assess long term neurofunction (Morris water maze, Rota rod and open field) along with brain infarct measurement. Overall CGP 35348 has improved the motor function in male and female albino mice but effects were more pronounced in female albino mice. In open field, CGP 35348 treated female albino mice had demonstrated poor exploratory behavior. During Morris water maze test, gender specific effects were observed as CGP 35348 had improved spatial learning and memory and swimming speed in male albino mice but had no effect in female albino mice following hypoxia ischemia encephalopathy (HIE). We concluded that GABAB receptor antagonists CGP 35348 can be used to improve gender based spatial memory. Q. Gillani, M. Ali, and F. Iqbal Copyright © 2014 Q. Gillani et al. All rights reserved. Association between Peripheral Oxidative Stress and White Matter Damage in Acute Traumatic Brain Injury Thu, 03 Apr 2014 13:04:13 +0000 The oxidative stress is believed to be one of the mechanisms involved in the neuronal damage after acute traumatic brain injury (TBI). However, the disease severity correlation between oxidative stress biomarker level and deep brain microstructural changes in acute TBI remains unknown. In present study, twenty-four patients with acute TBI and 24 healthy volunteers underwent DTI. The peripheral blood oxidative biomarkers, like serum thiol and thiobarbituric acid-reactive substances (TBARS) concentrations, were also obtained. The DTI metrics of the deep brain regions, as well as the fractional anisotropy (FA) and apparent diffusion coefficient, were measured and correlated with disease severity, serum thiol, and TBARS levels. We found that patients with TBI displayed lower FAs in deep brain regions with abundant WMs and further correlated with increased serum TBARS level. Our study has shown a level of anatomic detail to the relationship between white matter (WM) damage and increased systemic oxidative stress in TBI which suggests common inflammatory processes that covary in both the peripheral and central reactions after TBI. Wei-Ming Lin, Meng-Hsiang Chen, Hung-Chen Wang, Cheng-Hsien Lu, Pei-Chin Chen, Hsiu-Ling Chen, Nai-Wen Tsai, Yu-Jih Su, Shau-Hsuan Li, Chia-Te Kung, Tsui-Min Chiu, Hsu-Huei Weng, and Wei-Che Lin Copyright © 2014 Wei-Ming Lin et al. All rights reserved. Involvement of Endocytosis and Alternative Splicing in the Formation of the Pathological Process in the Early Stages of Parkinson’s Disease Thu, 03 Apr 2014 12:28:23 +0000 Parkinson’s disease (PD) is the one of most widespread neurodegenerative pathologies. Because of the impossibility of studying the endogenous processes that occur in the brain of patients with PD in the presymptomatic stage, the mechanisms that trigger the disease remain unknown. Thus, the identification of the processes that play an important role in the early stages of the disease in these patients is extremely difficult. In this context, we performed a whole-transcriptome analysis of the peripheral blood of untreated patients with stage 1 PD (Hoehn-Yahr scale). We demonstrated a significant change in the levels of transcripts included in the large groups of processes associated with the functioning of the immune system and cellular transport. Moreover, a significant change in the splicing of genes involved in cellular-transport processes was shown in our study. Anelya Kh. Alieva, Maria I. Shadrina, Elena V. Filatova, Aleksey V. Karabanov, Sergey N. Illarioshkin, Svetlana A. Limborska, and Petr A. Slominsky Copyright © 2014 Anelya Kh. Alieva et al. All rights reserved. Facing Contrast-Enhancing Gliomas: Perfusion MRI in Grade III and Grade IV Gliomas according to Tumor Area Thu, 03 Apr 2014 08:11:46 +0000 Tumoral neoangiogenesis characterizes high grade gliomas. Relative Cerebral Blood Volume (rCBV), calculated with Dynamic Susceptibility Contrast (DSC) Perfusion-Weighted Imaging (PWI), allows for the estimation of vascular density over the tumor bed. The aim of the study was to characterize putative tumoral neoangiogenesis via the study of maximal rCBV with a Region of Interest (ROI) approach in three tumor areas—the contrast-enhancing area, the nonenhancing tumor, and the high perfusion area on CBV map—in patients affected by contrast-enhancing glioma (grades III and IV). Twenty-one patients were included: 15 were affected by grade IV and 6 by grade III glioma. Maximal rCBV values for each patient were averaged according to glioma grade. Although rCBV from contrast-enhancement and from nonenhancing tumor areas was higher in grade IV glioma than in grade III (5.58 and 2.68; 3.01 and 2.2, resp.), the differences were not significant. Instead, rCBV recorded in the high perfusion area on CBV map, independently of tumor compartment, was significantly higher in grade IV glioma than in grade III (7.51 versus 3.78, ). In conclusion, neoangiogenesis encompasses different tumor compartments and CBV maps appear capable of best characterizing the degree of neovascularization. Facing contrast-enhancing brain tumors, areas of high perfusion on CBV maps should be considered as the reference areas to be targeted for glioma grading. Anna Luisa Di Stefano, Niels Bergsland, Giulia Berzero, Lisa Farina, Elisa Rognone, Matteo Gastaldi, Domenico Aquino, Alessandro Frati, Francesco Tomasello, Mauro Ceroni, Enrico Marchioni, and Stefano Bastianello Copyright © 2014 Anna Luisa Di Stefano et al. All rights reserved. Dissociable Self Effects for Emotion Regulation: A Study of Chinese Major Depressive Outpatients Thu, 03 Apr 2014 06:37:31 +0000 Reappraisal is an adaptive emotion regulation strategy while the role of self-perspective in reappraisal process of depressed patients is largely unknown in terms of goals (valence/arousal) and tactics (detachment/immersion). In this study, 12 depressed individuals and 15 controls were scanned with MRI during which they either attend naturally to emotional stimuli, or adopt detachment/immersion strategy. Behaviorally, no group differences in self-reported emotion regulation effectiveness were found. In addition, we observed that (1) patients were less able to downregulate amygdala activation with recruitment of more dorsal lateral prefrontal cortex (dlPFC) when adopting detachment strategy regardless of valence, and this preserved ability to regulate emotion was inversely associated with severity of symptoms; (2) patients had deficits in upregulating amygdala activation when adopting immersion strategy, with less inferior frontal gyrus (IFG) activation and strengthening coupling of dlPFC and ventral medial prefrontal cortex (vmPFC) with amygdala; (3) comparison between groups yielded that patients showed stronger vmPFC activation under either self-detached or self-immersed condition. In conclusion, impaired modulatory effects of amygdala in depressed patients are compensated with strengthening cognitive control resources, with dissociable effects for different self-perspectives in reappraisal. These results may help clarify the role of self-perspective underlying reappraisal in major depression. Xiaoxia Wang, Zhengzhi Feng, Daiquan Zhou, Xu Lei, Tongquan Liao, Li Zhang, Bing Ji, and Jing Li Copyright © 2014 Xiaoxia Wang et al. All rights reserved. An ANOCEF Genomic and Transcriptomic Microarray Study of the Response to Irinotecan and Bevacizumab in Recurrent Glioblastomas Wed, 02 Apr 2014 13:26:47 +0000 Background. We performed a retrospective study to assess whether the initial molecular characteristics of glioblastomas (GBMs) were associated with the response to the bevacizumab/irinotecan chemotherapy regimen given at recurrence. Results. Comparison of the genomic and gene expression profiles of the responders () and nonresponders () demonstrated only slight differences and could not identify any robust biomarkers associated with the response. In contrast, a significant association was observed between GBMs molecular subtypes and response rates. GBMs assigned to molecular subtype IGS-18 and to classical subtype had a lower response rate than those assigned to other subtypes. In an independent series of 33 patients, neither EGFR amplification nor CDKN2A deletion (which are frequent in IGS-18 and classical GBMs) was significantly associated with the response rate, suggesting that these two alterations are unlikely to explain the lower response rate of these GBMs molecular subtypes. Conclusion. Despite its limited sample size, the present study suggests that comparing the initial molecular profiles of responders and nonresponders might not be an effective strategy to identify biomarkers of the response to bevacizumab given at recurrence. Yet it suggests that the response rate might differ among GBMs molecular subtypes. Julien Laffaire, Anna Luisa Di Stefano, Olivier Chinot, Ahmed Idbaih, Jaime Gallego Perez-Larraya, Yannick Marie, Nadia Vintonenko, Blandine Boisselier, Patrizia Farina, Jean-Yves Delattre, Dominique Figarella-Branger, Jérôme Honnorat, Marc Sanson, and François Ducray Copyright © 2014 Julien Laffaire et al. All rights reserved. An Overview of Fotemustine in High-Grade Gliomas: From Single Agent to Association with Bevacizumab Mon, 31 Mar 2014 10:12:39 +0000 Fotemustine is a third-generation nitrosourea showing efficacy in various types of tumors such as melanoma and glioma. We reviewed the most important studies on fotemustine treatment in glioma patients analyzing its pharmacological profile and its activity and safety. Fotemustine was used as single agent or in association with new targeted drugs such as bevacizumab; fotemustine was used both as first-line chemotherapy before temozolomide era and in refractory-temozolomide patients during temozolomide era. Finally, analyzing and comparing the activity and safety of fotemustine alone or in combination with bevacizumab versus other nitrosoureas such as lomustine, we may suggest that the combination treatment with bevacizumab and fotemustine may be active and tolerable in patients with high grade gliomas. Giuseppe Lombardi, Patrizia Farina, Alessandro Della Puppa, Diego Cecchin, Ardi Pambuku, Luisa Bellu, and Vittorina Zagonel Copyright © 2014 Giuseppe Lombardi et al. All rights reserved. Assessing Response Using -MIBI Early after Interstitial Chemotherapy with Carmustine-Loaded Polymers in Glioblastoma Multiforme: Preliminary Results Thu, 27 Mar 2014 16:32:52 +0000 Introduction. Early signs of response after applying wafers of carmustine-loaded polymers (gliadel) are difficult to assess with imaging because of time-related imaging changes. -sestamibi (MIBI) brain single-photon emission tomography (SPET) has reportedly been used to reveal areas of cellularity distinguishing recurrent neoplasm from radionecrosis. Our aim was to explore the role of MIBI SPET in assessing response soon after gliadel application in glioblastoma multiforme (GBM). Methods. We retrospectively reviewed the charts on 28 consecutive patients with a radiological diagnosis of GBM who underwent MIBI SPET/CT before surgery (with intracavitary gliadel placement in 17 patients), soon after surgery, and at 4 months. The area of uptake was selected using a volume of interest that was then mirrored contralaterally to obtain a semiquantitative ratio. Results. After adjusting for ratio at the baseline, the effect of treatment (gliadel versus non-gliadel) was not statistically significant. Soon after surgery, however, 100% of patients treated with gliadel had a decreased ratio, as opposed to 62.5% of patients in the non-gliadel group . The difference between ratios of patients with radical versus partial resection reached statistical significance by a small margin . Conclusions. These data seem to suggest that the MIBI ratio could be a valuable tool for monitoring the effect of gliadel early after surgery. D. Cecchin, I. Schiorlin, A. Della Puppa, G. Lombardi, P. Zucchetta, V. Bodanza, M. P. Gardiman, G. Rolma, A. C. Frigo, and F. Bui Copyright © 2014 D. Cecchin et al. All rights reserved. Peripheral Leukocyte Apoptosis in Patients with Parkinsonism: Correlation with Clinical Characteristics and Neuroimaging Findings Wed, 26 Mar 2014 00:00:00 +0000 Apoptosis of both brain neurons and peripheral blood leukocyte is believed to be an important biomarker for evaluating the functional status of Parkinson’s disease (PD). However, their correlation remains unknown. A better understanding of the pathophysiology of neurodegeneration is essential for the treatment and prevention of PD. The present study demonstrated that leukocyte apoptosis is significantly higher in PD patients and is associated with central dopamine neuron loss by using -TRODAT-1 SPECT. The leukocyte apoptosis and striatal dopamine transporter uptake ratios were further associated with increased severity and longer duration of disease. The interaction between brain and systemic inflammation may be responsible for the neurodegenerative disease progression. Wei-Che Lin, Nai-Wen Tsai, Yung-Cheng Huang, Kuei-Yueh Cheng, Hsiu-Ling Chen, Shau-Hsuan Li, Chia-Te Kung, Yu-Jih Su, Wei-Ming Lin, Meng-Hsiang Chen, Tsui-Min Chiu, I-Hsiao Yang, and Cheng-Hsien Lu Copyright © 2014 Wei-Che Lin et al. All rights reserved. Does rTMS Alter Neurocognitive Functioning in Patients with Panic Disorder/Agoraphobia? An fNIRS-Based Investigation of Prefrontal Activation during a Cognitive Task and Its Modulation via Sham-Controlled rTMS Tue, 18 Mar 2014 00:00:00 +0000 Objectives. Neurobiologically, panic disorder (PD) is supposed to be characterised by cerebral hypofrontality. Via functional near-infrared spectroscopy (fNIRS), we investigated whether prefrontal hypoactivity during cognitive tasks in PD-patients compared to healthy controls (HC) could be replicated. As intermittent theta burst stimulation (iTBS) modulates cortical activity, we furthermore investigated its ability to normalise prefrontal activation. Methods. Forty-four PD-patients, randomised to sham or verum group, received 15 iTBS-sessions above the left dorsolateral prefrontal cortex (DLPFC) in addition to psychoeducation. Before first and after last iTBS-treatment, cortical activity during a verbal fluency task was assessed via fNIRS and compared to the results of 23 HC. Results. At baseline, PD-patients showed hypofrontality including the DLPFC, which differed significantly from activation patterns of HC. However, verum iTBS did not augment prefrontal fNIRS activation. Solely after sham iTBS, a significant increase of measured fNIRS activation in the left inferior frontal gyrus (IFG) during the phonological task was found. Conclusion. Our results support findings that PD is characterised by prefrontal hypoactivation during cognitive performance. However, verum iTBS as an “add-on” to psychoeducation did not augment prefrontal activity. Instead we only found increased fNIRS activation in the left IFG after sham iTBS application. Possible reasons including task-related psychophysiological arousal are discussed. Saskia Deppermann, Nadja Vennewald, Julia Diemer, Stephanie Sickinger, Florian B. Haeussinger, Swantje Notzon, Inga Laeger, Volker Arolt, Ann-Christine Ehlis, Peter Zwanzger, and Andreas J. Fallgatter Copyright © 2014 Saskia Deppermann et al. All rights reserved. Abnormal Early Gamma Responses to Emotional Faces Differentiate Unipolar from Bipolar Disorder Patients Thu, 13 Mar 2014 12:39:52 +0000 This study investigates the cortical abnormalities of early emotion perception in patients with major depressive disorder (MDD) and bipolar disorder (BD) using gamma oscillations. Twenty-three MDD patients, twenty-five BD patients, and twenty-four normal controls were enrolled and their event-related magnetoencephalographic responses were recorded during implicit emotional tasks. Our results demonstrated abnormal gamma activity within 100 ms in the emotion-related regions (amygdala, orbitofrontal (OFC) cortex, anterior insula (AI), and superior temporal pole) in the MDD patients, suggesting that these patients may have dysfunctions or negativity biases in perceptual binding of emotional features at very early stage. Decreased left superior medial frontal cortex (smFC) responses to happy faces in the MDD patients were correlated with their serious level of depression symptoms, indicating that decreased smFC activity perhaps underlies irregular positive emotion processing in depressed patients. In the BD patients, we showed abnormal activation in visual regions (inferior/middle occipital and middle temporal cortices) which responded to emotional faces within 100 ms, supporting that the BD patients may hyperactively respond to emotional features in perceptual binding. The discriminant function of gamma activation in the left smFC, right medial OFC, right AI/inferior OFC, and the right precentral cortex accurately classified 89.6% of patients as unipolar/bipolar disorders. T. Y. Liu, Y. S. Chen, T. P. Su, J. C. Hsieh, and L. F. Chen Copyright © 2014 T. Y. Liu et al. All rights reserved. Fear Processing in Dental Phobia during Crossmodal Symptom Provocation: An fMRI Study Tue, 11 Mar 2014 11:42:01 +0000 While previous studies successfully identified the core neural substrates of the animal subtype of specific phobia, only few and inconsistent research is available for dental phobia. These findings might partly relate to the fact that, typically, visual stimuli were employed. The current study aimed to investigate the influence of stimulus modality on neural fear processing in dental phobia. Thirteen dental phobics (DP) and thirteen healthy controls (HC) attended a block-design functional magnetic resonance imaging (fMRI) symptom provocation paradigm encompassing both visual and auditory stimuli. Drill sounds and matched neutral sinus tones served as auditory stimuli and dentist scenes and matched neutral videos as visual stimuli. Group comparisons showed increased activation in the insula, anterior cingulate cortex, orbitofrontal cortex, and thalamus in DP compared to HC during auditory but not visual stimulation. On the contrary, no differential autonomic reactions were observed in DP. Present results are largely comparable to brain areas identified in animal phobia, but also point towards a potential downregulation of autonomic outflow by neural fear circuits in this disorder. Findings enlarge our knowledge about neural correlates of dental phobia and may help to understand the neural underpinnings of the clinical and physiological characteristics of the disorder. Kevin Hilbert, Ricarda Evens, Nina Isabel Maslowski, Hans-Ulrich Wittchen, and Ulrike Lueken Copyright © 2014 Kevin Hilbert et al. All rights reserved. A Preliminary Study of the Influence of Age of Onset and Childhood Trauma on Cortical Thickness in Major Depressive Disorder Thu, 06 Mar 2014 09:56:18 +0000 Background. Major depressive disorder (MDD) neural underpinnings may differ based on onset age and childhood trauma. We assessed cortical thickness in patients who differed in age of MDD onset and examined trauma history influence. Methods. Adults with MDD () and controls (HC; ) underwent magnetic resonance imaging. Twenty patients had MDD onset 24 years of age (pediatric onset) and 16 had onset 25 years of age (adult onset). The MDD group was also subdivided into those with () and without () physical and/or sexual abuse as assessed by the Childhood Trauma Questionnaire (CTQ). Cortical thickness was analyzed with FreeSurfer software. Results. Thicker frontal pole and a tendency for thinner transverse temporal cortices existed in MDD. The former was driven by the pediatric onset group and abuse history (independently), particularly in the right frontal pole. Inverse correlations existed between CTQ scores and frontal pole cortex thickness. A similar inverse relation existed with left inferior and right superior parietal cortex thickness. The superior temporal cortex tended to be thinner in pediatric versus adult onset groups with childhood abuse. Conclusions. This preliminary work suggests neural differences between pediatric and adult MDD onset. Trauma history also contributes to cytoarchitectural modulation. Thickened frontal pole cortices as a compensatory mechanism in MDD warrant evaluation. Natalia Jaworska, Frank P. MacMaster, Ismael Gaxiola, Filomeno Cortese, Bradley Goodyear, and Rajamannar Ramasubbu Copyright © 2014 Natalia Jaworska et al. All rights reserved. Controversial Issues in Kyphoplasty and Vertebroplasty in Osteoporotic Vertebral Fractures Tue, 04 Mar 2014 13:05:44 +0000 Kyphoplasty (KP) and vertebroplasty (VP) have been successfully employed for many years for the treatment of osteoporotic vertebral fractures. The purpose of this review is to resolve the controversial issues raised by the two randomized trials that claimed no difference between VP and SHAM procedure. In particular we compare nonsurgical management (NSM) and KP and VP, in terms of clinical parameters (pain, disability, quality of life, and new fractures), cost-effectiveness, radiological variables (kyphosis correction and vertebral height restoration), and VP versus KP for cement extravasation and complications profile. Cement types and optimal filling are analyzed and technological innovations are presented. Finally unipedicular/bipedicular techniques are compared. Conclusion. VP and KP are superior to NSM in clinical and radiological parameters and probably more cost-effective. KP is superior to VP in sagittal balance improvement and cement leaking. Complications are rare but serious adverse events have been described, so caution should be exerted. Unilateral procedures should be pursued whenever feasible. Upcoming randomized trials (CEEP, OSTEO-6, STIC-2, and VERTOS IV) will provide the missing link. Ioannis D. Papanastassiou, Andreas Filis, Maria A. Gerochristou, and Frank D. Vrionis Copyright © 2014 Ioannis D. Papanastassiou et al. All rights reserved. Reduced Amygdala Volume Is Associated with Deficits in Inhibitory Control: A Voxel- and Surface-Based Morphometric Analysis of Comorbid PTSD/Mild TBI Mon, 03 Mar 2014 16:53:13 +0000 A significant portion of previously deployed combat Veterans from Operation Enduring Freedom and Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) are affected by comorbid posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI). Despite this fact, neuroimaging studies investigating the neural correlates of cognitive dysfunction within this population are almost nonexistent, with the exception of research examining the neural correlates of diagnostic PTSD or TBI. The current study used both voxel-based and surface-based morphometry to determine whether comorbid PTSD/mTBI is characterized by altered brain structure in the same regions as observed in singular diagnostic PTSD or TBI. Furthermore, we assessed whether alterations in brain structures in these regions were associated with behavioral measures related to inhibitory control, as assessed by the Go/No-go task, self-reports of impulsivity, and/or PTSD or mTBI symptoms. Results indicate volumetric reductions in the bilateral anterior amygdala in our comorbid PTSD/mTBI sample as compared to a control sample of OEF/OIF Veterans with no history of mTBI and/or PTSD. Moreover, increased volume reduction in the amygdala predicted poorer inhibitory control as measured by performance on the Go/No-go task, increased self-reported impulsivity, and greater symptoms associated with PTSD. These findings suggest that alterations in brain anatomy in OEF/OIF/OND Veterans with comorbid PTSD/mTBI are associated with both cognitive deficits and trauma symptoms related to PTSD. B. E. Depue, J. H. Olson-Madden, H. R. Smolker, M. Rajamani, L. A. Brenner, and M. T. Banich Copyright © 2014 B. E. Depue et al. All rights reserved. Diffusion Tensor Imaging Studies on Chinese Patients with Social Anxiety Disorder Mon, 03 Mar 2014 16:50:44 +0000 The aim of this study was to explore white-matter disruption in social anxiety disorder (SAD) patients by using diffusion tensor imaging (DTI) and to investigate the relationship between cerebral abnormalities and the severity of the symptoms. Eighteen SAD patients and age- and gender-matched healthy controls were recruited. DTI scans were performed to measure fractional anisotropy (FA) and apparent diffusion coefficient (ADC) for each subject. We used voxel-based analysis to determine the differences of FA and ADC values between the two groups with two-sample -tests. The SAD patient showed significantly decreased FA values in the white matter of the left insula, left inferior frontal gyrus, left middle temporal gyrus, and left inferior parietal gyrus and increased ADC values in the left insula, bilateral inferior frontal gyrus, bilateral middle temporal gyrus, and left inferior parietal gyrus. In SAD patients, we observed a significant negative correlation between FA values in the left insula and the total LSAS scores and a positive correlation between the ADC values in the left inferior frontal gyrus and the total LSAS scores. Above results suggested that white-matter microstructural changes might contribute to the neuropathology of SAD. Changjian Qiu, Chunyan Zhu, Jingna Zhang, Xiaojing Nie, Yuan Feng, Yajing Meng, Ruizhi Wu, Xiaoqi Huang, Wei Zhang, and Qiyong Gong Copyright © 2014 Changjian Qiu et al. All rights reserved. Designs and Techniques That Improve the Pullout Strength of Pedicle Screws in Osteoporotic Vertebrae: Current Status Mon, 03 Mar 2014 06:52:23 +0000 Osteoporosis is a medical condition affecting men and women of different age groups and populations. The compromised bone quality caused by this disease represents an important challenge when a surgical procedure (e.g., spinal fusion) is needed after failure of conservative treatments. Different pedicle screw designs and instrumentation techniques have been explored to enhance spinal device fixation in bone of compromised quality. These include alterations of screw thread design, optimization of pilot hole size for non-self-tapping screws, modification of the implant’s trajectory, and bone cement augmentation. While the true benefits and limitations of any procedure may not be realized until they are observed in a clinical setting, axial pullout tests, due in large part to their reproducibility and ease of execution, are commonly used to estimate the device’s effectiveness by quantifying the change in force required to remove the screw from the body. The objective of this investigation is to provide an overview of the different pedicle screw designs and the associated surgical techniques either currently utilized or proposed to improve pullout strength in osteoporotic patients. Mechanical comparisons as well as potential advantages and disadvantages of each consideration are provided herein. Thomas M. Shea, Jake Laun, Sabrina A. Gonzalez-Blohm, James J. Doulgeris, William E. Lee III, Kamran Aghayev, and Frank D. Vrionis Copyright © 2014 Thomas M. Shea et al. All rights reserved. Surface-Based Regional Homogeneity in First-Episode, Drug-Naïve Major Depression: A Resting-State fMRI Study Tue, 25 Feb 2014 11:30:15 +0000 Background. Previous volume-based regional homogeneity (ReHo) studies neglected the intersubject variability in cortical folding patterns. Recently, surface-based ReHo was developed to reduce the intersubject variability and to increase statistical power. The present study used this novel surface-based ReHo approach to explore the brain functional activity differences between first-episode, drug-naïve MDD patients and healthy controls. Methods. Thirty-three first-episode, drug-naïve MDD patients and 32 healthy controls participated in structural and resting-state fMRI scans. MDD patients were rated with a 17-item Hamilton Rating Scale for Depression prior to the scan. Results. In comparison with the healthy controls, MDD patients showed reduced surface-based ReHo in the left insula. There was no increase in surface-based ReHo in MDD patients. The surface-based ReHo value in the left insula was not significantly correlated with the clinical information or the depressive scores in the MDD group. Conclusions. The decreased surface-based ReHo in the left insula in MDD may lead to the abnormal top-down cortical-limbic regulation of emotional and cognitive information. The surface-based ReHo may be a useful index to explore the pathophysiological mechanism of MDD. Hui-Jie Li, Xiao-Hua Cao, Xing-Ting Zhu, Ai-Xia Zhang, Xiao-Hui Hou, Yong Xu, Xi-Nian Zuo, and Ke-Rang Zhang Copyright © 2014 Hui-Jie Li et al. All rights reserved. Percutaneous Cement-Augmented Screws Fixation in the Fractures of the Aging Spine: Is It the Solution? Thu, 20 Feb 2014 12:50:15 +0000 Introduction. Management of elderly patients with thoracolumbar fractures is still challenging due to frequent osteoporosis and risk of screws pull-out. The aim of this study was to evaluate results of a percutaneous-only procedure to treat these fragile patients using cement-augmented screws. Methods. 12 patients diagnosed with a thoracolumbar fracture associated with an important loss of bone stock were included in this prospective study. Surgical procedure included systematically a percutaneous osteosynthesis using cemented fenestrated screws. When necessary, additional anterior support was performed using a kyphoplasty procedure. Clinical and radiographic evaluations were performed using CT scan. Results. On the whole series, 15 fractures were diagnosed and 96 cemented screws were inserted. The difference between the pre- and postoperative vertebral kyphosis was statistically significant (12.9° versus 4.4°, ). No extrapedicular screw was reported and one patient was diagnosed with a cement-related pulmonary embolism. During follow-up period, no infectious complications, implant failures, or pull-out screws were noticed. Discussion. Aging spine is becoming an increasing public health issue. Management of these patients requires specific attention due to the augmented risk of complications. Using percutaneous-only screws fixation with cemented screw provides satisfactory results. A rigorous technique is mandatory in order to achieve best outcomes. Sébastien Pesenti, Benjamin Blondel, Emilie Peltier, Tarek Adetchessi, Henry Dufour, and Stéphane Fuentes Copyright © 2014 Sébastien Pesenti et al. All rights reserved. Proton Pump Inhibition Increases Rapid Eye Movement Sleep in the Rat Wed, 19 Feb 2014 11:41:10 +0000 Increased bodily CO2 concentration alters cellular pH as well as sleep. The proton pump, which plays an important role in the homeostatic regulation of cellular pH, therefore, may modulate sleep. We investigated the effects of the proton pump inhibitor “lansoprazole” on sleep-wakefulness. Male Wistar rats were surgically prepared for chronic polysomnographic recordings. Two different doses of lansoprazole (low: 1 mg/kg; high: 10 mg/kg) were injected intraperitoneally in the same animal () and sleep-wakefulness was recorded for 6 hrs. The changes in sleep-wakefulness were compared statistically. Percent REM sleep amount in the vehicle and lansoprazole low dose groups was and , respectively, which increased significantly in the lansoprazole high dose group by 31.75% (from vehicle) and 34.21% (from low dose). Also, REM sleep episode numbers significantly increased in lansoprazole high dose group. Further, the sodium-hydrogen exchanger blocker “amiloride” (10 mg/kg; i.p.) () did not alter sleep-wake architecture. Our results suggest that the proton pump plays an important role in REM sleep modulation and supports our view that REM sleep might act as a sentinel to help maintain normal CO2 level for unperturbed sleep. Munazah Fazal Qureshi and Sushil K. Jha Copyright © 2014 Munazah Fazal Qureshi and Sushil K. Jha. All rights reserved. Systematic Review on Surgical and Nonsurgical Treatment of Type II Odontoid Fractures in the Elderly Mon, 10 Feb 2014 09:25:45 +0000 Odontoid fractures type II according to Anderson and d’Alonzo are not uncommon in the elderly patients. Still, due to the paucity of evidence the published treatment guidelines are far from equivocal. This systematic review focuses on the published results of type II odontoid fracture treatment in the elderly with regard to survival, nonunion, and complications. After a systematic literature research 38 publications were included. A cumulative analysis of 1284 published cases found greater survival if elderly patients with odontoid fractures type II received surgical treatment (RR = 0.64). With regard to nonunion in 669 published cases primary posterior fusion had the best fusion results. The systematic literature review came to the following conclusions. (1) Surgical stabilisation of odontoid fractures type II improves survival in patients between 65 and 85 years of age compared to nonsurgical treatment. (2) Posterior atlantoaxial fusion for odontoid fractures type II in the elderly has the greatest bony union rate. (3) Odontoid nonunion is not associated with worse clinical or functional results in the elderly. (4) The complication rate of nonsurgical treatment is similar to the complication rate of surgical treatment of odontoid fractures type II in the elderly. Yohan Robinson, Anna-Lena Robinson, and Claes Olerud Copyright © 2014 Yohan Robinson et al. All rights reserved. Mesenchymal Stem Cells Expressing Brain-Derived Neurotrophic Factor Enhance Endogenous Neurogenesis in an Ischemic Stroke Model Wed, 05 Feb 2014 13:52:01 +0000 Numerous studies have reported that mesenchymal stem cells (MSCs) can ameliorate neurological deficits in ischemic stroke models. Among the various hypotheses that have been suggested to explain the therapeutic mechanism underlying these observations, neurogenesis is thought to be critical. To enhance the therapeutic benefits of human bone marrow-derived MSCs (hBM-MSCs), we efficiently modified hBM-MSCs by introduction of the brain-derived neurotrophic factor (BDNF) gene via adenoviral transduction mediated by cell-permeable peptides and investigated whether BDNF-modified hBM-MSCs (MSCs-BDNF) contributed to functional recovery and endogenous neurogenesis in a rat model of middle cerebral artery occlusion (MCAO). Transplantation of MSCs induced the proliferation of 5-bromo-2′-deoxyuridine (BrdU-) positive cells in the subventricular zone. Transplantation of MSCs-BDNF enhanced the proliferation of endogenous neural stem cells more significantly, while suppressing cell death. Newborn cells differentiated into doublecortin (DCX-) positive neuroblasts and Neuronal Nuclei (NeuN-) positive mature neurons in the subventricular zone and ischemic boundary at higher rates in animals with MSCs-BDNF compared with treatment using solely phosphate buffered saline (PBS) or MSCs. Triphenyltetrazolium chloride staining and behavioral analysis revealed greater functional recovery in animals with MSCs-BDNF compared with the other groups. MSCs-BDNF exhibited effective therapeutic potential by protecting cell from apoptotic death and enhancing endogenous neurogenesis. Chang Hyun Jeong, Seong Muk Kim, Jung Yeon Lim, Chung Heon Ryu, Jin Ae Jun, and Sin-Soo Jeun Copyright © 2014 Chang Hyun Jeong et al. All rights reserved. A Mushroom Extract Piwep from Phellinus igniarius Ameliorates Experimental Autoimmune Encephalomyelitis by Inhibiting Immune Cell Infiltration in the Spinal Cord Mon, 27 Jan 2014 07:25:49 +0000 The present study aimed to evaluate the therapeutic potential of a mushroom extract from Phellinus igniarius in an animal model of multiple sclerosis. The medicinal mushroom, Phellinus igniarius, contains biologically active compounds that modulate the human immune system. Experimental autoimmune encephalomyelitis (EAE) was induced by immunization with myelin oligodendrocyte glycoprotein (MOG 35–55) in C57BL/6 female mice. A water-ethanol extract of Phellinus igniarius (Piwep) was delivered intraperitoneally every other day for the entire experimental course. Three weeks after the initial immunization, demyelination and immune cell infiltration in the spinal cord were examined. Piwep injection profoundly decreased the daily incidence rate and clinical score of EAE. The Piwep-mediated inhibition of the clinical course of EAE was accompanied by suppression of demyelination and infiltration of encephalitogenic immune cells including CD4+ T cells, CD8+ T cells, macrophages, and B cells in the spinal cord. Piwep reduced expression of vascular cell adhesion molecule-1 (VCAM-1) in the spinal cord and integrin- in the lymph node of EAE mice. Piwep also inhibited proliferation of lymphocytes and secretion of interferon- in the lymph node of EAE mice. The results suggest that a mushroom extract, Piwep, may have a high therapeutic potential for ameliorating multiple sclerosis progression. Lan Li, Guang Wu, Bo Young Choi, Bong Geom Jang, Jin Hee Kim, Gi Ho Sung, Jae Youl Cho, Sang Won Suh, and Hyoung Jin Park Copyright © 2014 Lan Li et al. All rights reserved. Stereotactic Radiosurgery with Neoadjuvant Embolization of Larger Arteriovenous Malformations: An Institutional Experience Wed, 22 Jan 2014 14:09:48 +0000 Objective. This study investigates the safety and efficacy of a multimodality approach combining staged endovascular embolizations with subsequent SRS for the management of larger AVMs. Methods. Ninety-five patients with larger AVMs were treated with staged endovascular embolization followed by SRS between 1996 and 2011. Results. The median volume of AVM in this series was 28 cm3 and 47 patients (48%) were Spetzler-Martin grade IV or V. Twenty-seven patients initially presented with hemorrhage. Sixty-one patients underwent multiple embolizations while a single SRS session was performed in 64 patients. The median follow-up after SRS session was 32 months (range 9–136 months). Overall procedural complications occurred in 14 patients. There were 13 minor neurologic complications and 1 major complication (due to embolization) while four patients had posttreatment hemorrhage. Thirty-eight patients (40%) were cured radiographically. The postradiosurgery actuarial rate of obliteration was 45% at 5 years, 56% at 7 years, and 63% at 10 years. In multivariate analysis, larger AVM size, deep venous drainage, and the increasing number of embolization/SRS sessions were negative predictors of obliteration. The number of embolizations correlated positively with the number of stereotactic radiosurgeries (). Conclusions. Multimodality endovascular and radiosurgical approach is an efficacious treatment strategy for large AVM. Richard Dalyai, Thana Theofanis, Robert M. Starke, Nohra Chalouhi, George Ghobrial, Pascal Jabbour, Aaron S. Dumont, L. Fernando Gonzalez, David S. Gordon, Robert H. Rosenwasser, and Stavropoula I. Tjoumakaris Copyright © 2014 Richard Dalyai et al. All rights reserved. Notch1 and 4 Signaling Responds to an Increasing Vascular Wall Shear Stress in a Rat Model of Arteriovenous Malformations Mon, 20 Jan 2014 12:09:29 +0000 Notch signaling is suggested to promote the development and maintenance of cerebral arteriovenous malformations (AVMs), and an increasing wall shear stress (WSS) contributes to AVM rupture. Little is known about whether WSS impacts Notch signaling, which is important for understanding the angiogenesis of AVMs. WSS was measured in arteriovenous fistulas (AVF) surgically created in 96 rats at different time points over a period of 84 days. The expression of Notch receptors 1 and 4 and their ligands, Delta1 and 4, Jagged1, and Notch downstream gene target Hes1 was quantified in “nidus” vessels. The interaction events between Notch receptors and their ligands were quantified using proximity ligation assay. There was a positive correlation between WSS and time (; ). The expression of Notch receptors and their ligands was upregulated following AVF formation. There was a positive correlation between time and the number of interactions between Notch receptors and their ligands aftre AVF formation (, ) and a positive correlation between WSS and the number of interactions between Notch receptors and their ligands (, ). In conclusion, an increasing WSS may contribute to the angiogenesis of AVMs by activation of Notch signaling. Jian Tu, Yang Li, and Zhiqiang Hu Copyright © 2014 Jian Tu et al. All rights reserved. Neuroanatomical Classification in a Population-Based Sample of Psychotic Major Depression and Bipolar I Disorder with 1 Year of Diagnostic Stability Sun, 19 Jan 2014 13:55:13 +0000 The presence of psychotic features in the course of a depressive disorder is known to increase the risk for bipolarity, but the early identification of such cases remains challenging in clinical practice. In the present study, we evaluated the diagnostic performance of a neuroanatomical pattern classification method in the discrimination between psychotic major depressive disorder (MDD), bipolar I disorder (BD-I), and healthy controls (HC) using a homogenous sample of patients at an early course of their illness. Twenty-three cases of first-episode psychotic mania (BD-I) and 19 individuals with a first episode of psychotic MDD whose diagnosis remained stable during 1 year of followup underwent 1.5 T MRI at baseline. A previously validated multivariate classifier based on support vector machine (SVM) was employed and measures of diagnostic performance were obtained for the discrimination between each diagnostic group and subsamples of age- and gender-matched controls recruited in the same neighborhood of the patients. Based on T1-weighted images only, the SVM-classifier afforded poor discrimination in all 3 pairwise comparisons: BD-I versus HC; MDD versus HC; and BD-I versus MDD. Thus, at the population level and using structural MRI only, we failed to achieve good discrimination between BD-I, psychotic MDD, and HC in this proof of concept study. Mauricio H. Serpa, Yangming Ou, Maristela S. Schaufelberger, Jimit Doshi, Luiz K. Ferreira, Rodrigo Machado-Vieira, Paulo R. Menezes, Marcia Scazufca, Christos Davatzikos, Geraldo F. Busatto, and Marcus V. Zanetti Copyright © 2014 Mauricio H. Serpa et al. All rights reserved. Adverse Prognostic Factors and Optimal Intervention Time for Kyphoplasty/Vertebroplasty in Osteoporotic Fractures Sun, 19 Jan 2014 07:25:05 +0000 Introduction. While evidence supports the efficacy of vertebral augmentation (kyphoplasty and vertebroplasty) for the treatment of osteoporotic fractures, randomized trials disputed the value of vertebroplasty. The aim of this analysis is to determine the subset of patients that may not benefit from surgical intervention and find the optimal intervention time. Methods. 27 prospective multiple-arm studies with cohorts of more than 20 patients were included in this meta-analysis. We hereby report the results from the metaregression and subset analysis of those trials reporting on treatment of osteoporotic fractures with kyphoplasty and/or vertebroplasty. Results. Early intervention (first 7 weeks after fracture) yielded more pain relief. However, spontaneous recovery was encountered in hyperacute fractures (less than 2 weeks old). Patients suffering from thoracic fractures or severely deformed vertebrae tended to report inferior results. We also attempted to formulate a treatment algorithm. Conclusion. Intervention in the hyperacute period should not be pursued, while augmentation after 7 weeks yields less consistent results. In cases of thoracic fractures and significant vertebral collapse, surgeons or interventional radiologists may resort earlier to operation and be less conservative, although those parameters need to be addressed in future randomized trials. Ioannis D. Papanastassiou, Andreas Filis, Kamran Aghayev, Zinon T. Kokkalis, Maria A. Gerochristou, and Frank D. Vrionis Copyright © 2014 Ioannis D. Papanastassiou et al. All rights reserved. Continuous Selective Intra-Arterial Application of Nimodipine in Refractory Cerebral Vasospasm due to Aneurysmal Subarachnoid Hemorrhage Thu, 16 Jan 2014 07:18:02 +0000 Background. Cerebral vasospasm is one of the leading courses for disability in aneurysmal subarachnoid hemorrhage. Effective treatment of vasospasm is therefore one of the main priorities for these patients. We report about a case series of continuous intra-arterial infusion of the calcium channel antagonist nimodipine for 1–5 days on the intensive care unit. Methods. In thirty patients with aneurysmal subarachnoid hemorrhage and refractory vasospasm continuous infusion of nimodipine was started on the neurosurgical intensive care unit. The effect of nimodipine on brain perfusion, cerebral blood flow, brain tissue oxygenation, and blood flow velocity in cerebral arteries was monitored. Results. Based on Hunt & Hess grades on admission, 83% survived in a good clinical condition and 23% recovered without an apparent neurological deficit. Persistent ischemic areas were seen in 100% of patients with GOS 1–3 and in 69% of GOS 4-5 patients. Regional cerebral blood flow and computed tomography perfusion scanning showed adequate correlation with nimodipine application and angiographic vasospasm. Transcranial Doppler turned out to be unreliable with interexaminer variance and failure of detecting vasospasm or missing the improvement. Conclusion. Local continuous intra-arterial nimodipine treatment for refractory cerebral vasospasm after aSAH can be recommended as a low-risk treatment in addition to established endovascular therapies. Stephanie Ott, Sheila Jedlicka, Stefan Wolf, Mozes Peter, Christine Pudenz, Patrick Merker, Ludwig Schürer, and Christianto Benjamin Lumenta Copyright © 2014 Stephanie Ott et al. All rights reserved. Long-Term Effects of Postearthquake Distress on Brain Microstructural Changes Tue, 14 Jan 2014 14:16:10 +0000 Stressful events can have both short- and long-term effects on the brain. Our recent investigation identified short-term white matter integrity (WMI) changes in 30 subjects soon after the Japanese earthquake. Our findings suggested that lower WMI in the right anterior cingulum (Cg) was a pre-existing vulnerability factor and increased WMI in the left anterior Cg and uncinate fasciculus (Uf) after the earthquake was an acquired sign of postearthquake distress. However, the long-term effects on WMI remained unclear. Here, we examined the 1-year WMI changes in 25 subjects to clarify long-term effects on the WMI. We found differential FAs in the right anterior Cg, bilateral Uf, left superior longitudinal fasciculus (SLF), and left thalamus, suggesting that synaptic enhancement and shrinkage were long-term effects. Additionally, the correlation between psychological measures related to postearthquake distress and the degree of WMI alternation in the right anterior Cg and the left Uf led us to speculate that temporal WMI changes in some subjects with emotional distress occurred soon after the disaster. We hypothesized that dynamic WMI changes predict a better prognosis, whereas persistently lower WMI is a marker of cognitive dysfunction, implying the development of anxiety disorders. Atsushi Sekiguchi, Yuka Kotozaki, Motoaki Sugiura, Rui Nouchi, Hikaru Takeuchi, Sugiko Hanawa, Seishu Nakagawa, Carlos Makoto Miyauchi, Tsuyoshi Araki, Atsushi Sakuma, Yasuyuki Taki, and Ryuta Kawashima Copyright © 2014 Atsushi Sekiguchi et al. All rights reserved. Neurotoxicants Are in the Air: Convergence of Human, Animal, and In Vitro Studies on the Effects of Air Pollution on the Brain Sun, 12 Jan 2014 00:00:00 +0000 In addition to increased morbidity and mortality caused by respiratory and cardiovascular diseases, air pollution may also negatively affect the brain and contribute to central nervous system diseases. Air pollution is a mixture comprised of several components, of which ultrafine particulate matter (UFPM; <100 nm) is of much concern, as these particles can enter the circulation and distribute to most organs, including the brain. A major constituent of ambient UFPM is represented by traffic-related air pollution, mostly ascribed to diesel exhaust (DE). Human epidemiological studies and controlled animal studies have shown that exposure to air pollution may lead to neurotoxicity. In addition to a variety of behavioral abnormalities, two prominent effects caused by air pollution are oxidative stress and neuroinflammation, which are seen in both humans and animals and are confirmed by in vitro studies. Among factors which can affect neurotoxic outcomes, age is considered the most relevant. Human and animal studies suggest that air pollution (and DE) may cause developmental neurotoxicity and may contribute to the etiology of neurodevelopmental disorders, including autistic spectrum disorders. In addition, air pollution exposure has been associated with increased expression of markers of neurodegenerative disease pathologies. Lucio G. Costa, Toby B. Cole, Jacki Coburn, Yu-Chi Chang, Khoi Dao, and Pamela Roque Copyright © 2014 Lucio G. Costa et al. All rights reserved. Effects of Stress and MDMA on Hippocampal Gene Expression Thu, 09 Jan 2014 08:56:05 +0000 MDMA (3,4-methylenedioxymethamphetamine) is a substituted amphetamine and popular drug of abuse. Its mood-enhancing short-term effects may prompt its consumption under stress. Clinical studies indicate that MDMA treatment may mitigate the symptoms of stress disorders such as posttraumatic stress syndrome (PTSD). On the other hand, repeated administration of MDMA results in persistent deficits in markers of serotonergic (5-HT) nerve terminals that have been viewed as indicative of 5-HT neurotoxicity. Exposure to chronic stress has been shown to augment MDMA-induced 5-HT neurotoxicity. Here, we examine the transcriptional responses in the hippocampus to MDMA treatment of control rats and rats exposed to chronic stress. MDMA altered the expression of genes that regulate unfolded protein binding, protein folding, calmodulin-dependent protein kinase activity, and neuropeptide signaling. In stressed rats, the gene expression profile in response to MDMA was altered to affect sensory processing and responses to tissue damage in nerve sheaths. Subsequent treatment with MDMA also markedly altered the genetic responses to stress such that the stress-induced downregulation of genes related to the circadian rhythm was reversed. The data support the view that MDMA-induced transcriptional responses accompany the persistent effects of this drug on neuronal structure/function. In addition, MDMA treatment alters the stress-induced transcriptional signature. Georg F. Weber, Bethann N. Johnson, Bryan K. Yamamoto, and Gary A. Gudelsky Copyright © 2014 Georg F. Weber et al. All rights reserved. GRIN2B Gene and Associated Brain Cortical White Matter Changes in Bipolar Disorder: A Preliminary Combined Platform Investigation Mon, 30 Dec 2013 18:55:20 +0000 Abnormalities in glutamate signaling and glutamate toxicity are thought to be important in the pathophysiology of bipolar disorder (BD). Whilst previous studies have found brain white matter changes in BD, there is paucity of data about how glutamatergic genes affect brain white matter integrity in BD. Based on extant neuroimaging data, we hypothesized that GRIN2B risk allele is associated with reductions of brain white matter integrity in the frontal, parietal, temporal, and occipital regions and cingulate gyrus in BD. Fourteen patients with BD and 22 healthy controls matched in terms of age, gender and handedness were genotyped using blood samples and underwent diffusion tensor imaging. Compared to G allele, brain FA values were significantly lower in BD patients with risk T allele in left frontal region (), right frontal region (), left parietal region (), left occipital region (), right occipital region (), and left cingulate gyrus (). Further elucidation of the interactions between different glutamate genes and their relationships with such structural, functional brain substrates will enhance our understanding of the link between dysregulated glutamatergic neurotransmission and neuroimaging endophenotypes in BD. Carissa Nadia Kuswanto, Min Yi Sum, Christopher Ren Zhi Thng, Yi Bin Zhang, Guo Liang Yang, Wieslaw Lucjan Nowinski, Yih Yian Sitoh, Chian Ming Low, and Kang Sim Copyright © 2013 Carissa Nadia Kuswanto et al. All rights reserved. Comparison of Neurologic and Radiographic Outcomes with Solitaire versus Merci/Penumbra Systems for Acute Stroke Intervention Mon, 30 Dec 2013 12:01:02 +0000 Background and Purpose. The Solitaire Flow Restoration was approved by the FDA in 2012 for mechanical thrombolysis of proximal occlusion of intracranial arteries. To compare the Solitaire FR device and the Merci/Penumbra (previously FDA approved) systems in terms of safety, clinical outcomes, and efficacy including radiographic brain parenchymal salvage. Methods. Thirty-one consecutive patients treated with the Solitaire and 20 patients with comparable baseline characteristics treated with Merci or Penumbra systems were included in the study. Primary outcome measures included recanalization rate and modified Rankin Scale score at followup. Secondary outcomes included length of procedure, incidence of symptomatic intracranial hemorrhage, 90-day mortality, and radiographic analysis of percentage area salvage. Results. Compared with the Merci/Penumbra group, the Solitaire group showed a statistically significant improvement in favorable outcomes (mRS ≤ 2) (69% versus 35%, ) and symptomatic ICH rate (0 versus 15%, ) with a trend towards higher recanalization rates (93.5% versus 75%, ) and shorter length of procedure (58.5 min versus 70.8 min, ). Radiographic comparison also showed a significantly larger area of salvage in the Solitaire group (81.9% versus 71.9%, ). Conclusion. Our study suggests that the Solitaire system allows faster, safer, and more efficient thrombectomy than Merci or Penumbra systems. Shannon Hann, Nohra Chalouhi, Robert Starke, Ashish Gandhe, Michael Koltz, Thana Theofanis, Pascal Jabbour, L. Fernando Gonzalez, Robert Rosenwasser, and Stavropoula Tjoumakaris Copyright © 2013 Shannon Hann et al. All rights reserved. Neuroprotective Activity of Thioctic Acid in Central Nervous System Lesions Consequent to Peripheral Nerve Injury Sun, 29 Dec 2013 16:24:37 +0000 Peripheral neuropathies are heterogeneous disorders presenting often with hyperalgesia and allodynia. This study has assessed if chronic constriction injury (CCI) of sciatic nerve is accompanied by increased oxidative stress and central nervous system (CNS) changes and if these changes are sensitive to treatment with thioctic acid. Thioctic acid is a naturally occurring antioxidant existing in two optical isomers (+)- and (−)-thioctic acid and in the racemic form. It has been proposed for treating disorders associated with increased oxidative stress. Sciatic nerve CCI was made in spontaneously hypertensive rats (SHRs) and in normotensive reference cohorts. Rats were untreated or treated intraperitoneally for 14 days with (+/−)-, (+)-, or (−)-thioctic acid. Oxidative stress, astrogliosis, myelin sheets status, and neuronal injury in motor and sensory cerebrocortical areas were assessed. Increase of oxidative stress markers, astrogliosis, and neuronal damage accompanied by a decreased expression of neurofilament were observed in SHR. This phenomenon was more pronounced after CCI. Thioctic acid countered astrogliosis and neuronal damage, (+)-thioctic acid being more active than (+/−)- or (−)-enantiomers. These findings suggest a neuroprotective activity of thioctic acid on CNS lesions consequent to CCI and that the compound may represent a therapeutic option for entrapment neuropathies. Daniele Tomassoni, Francesco Amenta, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Innocent E. Nwankwo, Alessandra Pacini, and Seyed Khosrow Tayebati Copyright © 2013 Daniele Tomassoni et al. All rights reserved. Atrophy and Primary Somatosensory Cortical Reorganization after Unilateral Thoracic Spinal Cord Injury: A Longitudinal Functional Magnetic Resonance Imaging Study Sun, 29 Dec 2013 14:38:31 +0000 The effects of traumatic spinal cord injury (SCI) on the changes in the central nervous system (CNS) over time may depend on the dynamic interaction between the structural integrity of the spinal cord and the capacity of the brain plasticity. Functional magnetic resonance imaging (fMRI) was used in a longitudinal study on five rhesus monkeys to observe cerebral activation during upper limb somatosensory tasks in healthy animals and after unilateral thoracic SCI. The changes in the spinal cord diameters were measured, and the correlations among time after the lesion, structural changes in the spinal cord, and primary somatosensory cortex (S1) reorganization were also determined. After SCI, activation of the upper limb in S1 shifted to the region which generally dominates the lower limb, and the rostral spinal cord transverse diameter adjacent to the lesion exhibited obvious atrophy, which reflects the SCI-induced changes in the CNS. A significant correlation was found among the time after the lesion, the spinal cord atrophy, and the degree of contralateral S1 reorganization. The results indicate the structural changes in the spinal cord and the dynamic reorganization of the cerebral activation following early SCI stage, which may help to further understand the neural plasticity in the CNS. Jia-Sheng Rao, Ma Manxiu, Can Zhao, Yue Xi, Zhao-Yang Yang, Liu Zuxiang, and Xiao-Guang Li Copyright © 2013 Jia-Sheng Rao et al. All rights reserved. Hippocampal Gene Expression of Deiodinases 2 and 3 and Effects of 3,5-Diiodo-L-Thyronine T2 in Mouse Depression Paradigms Tue, 10 Dec 2013 08:57:50 +0000 Central thyroid hormone signaling is important in brain function/dysfunction, including affective disorders and depression. In contrast to 3,3′,5-triiodo-L-thyronine (T3), the role of 3,5-diiodo-L-thyronine (T2), which until recently was considered an inactive metabolite of T3, has not been studied in these pathologies. However, both T3 and T2 stimulate mitochondrial respiration, a factor counteracting the pathogenesis of depressive disorder, but the cellular origins in the CNS, mechanisms, and kinetics of the cellular action for these two hormones are distinct and independent of each other. Here, Illumina and RT PCR assays showed that hippocampal gene expression of deiodinases 2 and 3, enzymes involved in thyroid hormone regulation, is increased in resilience to stress-induced depressive syndrome and after antidepressant treatment in mice that might suggest elevated T2 and T3 turnover in these phenotypes. In a separate experiment, bolus administration of T2 at the doses 750 and 1500 mcg/kg but not 250 mcg/kg in naive mice reduced immobility in a two-day tail suspension test in various settings without changing locomotion or anxiety. This demonstrates an antidepressant-like effect of T2 that could be exploited clinically. In a wider context, the current study suggests important central functions of T2, whose biological role only lately is becoming to be elucidated. Natalyia Markova, Anton Chernopiatko, Careen A. Schroeter, Dmitry Malin, Aslan Kubatiev, Sergey Bachurin, João Costa-Nunes, Harry M. W. Steinbusch, and Tatyana Strekalova Copyright © 2013 Natalyia Markova et al. All rights reserved. Endovascular Treatment of Cerebral Mycotic Aneurysm: A Review of the Literature and Single Center Experience Mon, 09 Dec 2013 09:48:41 +0000 The management of mycotic aneurysm has always been subject to controversy. The aim of this paper is to review the literature on the intracranial infected aneurysm from pathogenesis till management while focusing mainly on the endovascular interventions. This novel solution seems to provide additional benefits and long-term favorable outcomes. Mario Zanaty, Nohra Chalouhi, Robert M. Starke, Stavropoula Tjoumakaris, L. Fernando Gonzalez, David Hasan, Robert Rosenwasser, and Pascal Jabbour Copyright © 2013 Mario Zanaty et al. All rights reserved. Enhanced Intensity Dependence as a Marker of Low Serotonergic Neurotransmission in High Optimistic College Students Sun, 08 Dec 2013 14:36:25 +0000 Positive psychology focuses were on the merits of individuals, such as optimism and positive attitude, and the subsequent cultivation of these virtues. Optimism or pessimism is a significant predictor of physical health outcomes. The present study examined whether optimism or pessimism is associated with the loudness dependence of auditory evoked potentials (LDAEP), a biological indicator of serotonergic neurotransmission, for the N1, P2, and N1/P2 peaks in college students. The amplitudes and amplitude-stimulus intensity function (ASF) slopes of the N1, P2, and N1/P2 peaks were determined in the 24 (10 males) high optimistic and 24 (14 males) high pessimistic individuals. Significantly higher P2 ASF slopes were found in the optimistic group relative to the pessimistic group. Concerning peaks and ASF slopes of N1 and N1/P2, no significant differences were observed. Our results suggest that the serotonergic neurotransmission of the high optimistic college students was inferior to that of the pessimistic ones. Further investigations are needed to provide sufficient support for our results. Jibiao Zhang, Daxing Wu, Shuqiao Yao, Yunxuan Xu, and Xuejing Lu Copyright © 2013 Jibiao Zhang et al. All rights reserved. Cerebral Blood Flow Dynamics and Head-of-Bed Changes in the Setting of Subarachnoid Hemorrhage Mon, 25 Nov 2013 13:48:22 +0000 Head-of-bed (HOB) elevation is usually restricted in patients with aneurysmal subarachnoid hemorrhage (SAH). The goal of this study is to correlate HOB changes ( and ) with cerebral blood flow using transcranial Doppler (TCD) and thermal diffusion probe in SAH patients. Thirteen patients with SAH were prospectively enrolled in the study. Eight patients underwent placement of a thermal diffusion probe for regional CBF measurement. CBF values were measured with the patients in flat () and upright sitting positions () at days 3, 7, and 10. The average increase in blood flow velocity when changing HOB from to was 7.8% on day 3, 0.1% on day 7, and 13.1% on day 10. The middle cerebral artery had the least changes in velocity. The average regional CBF measurement was 22.7 ± 0.3 mL/100 g/min in the supine position and 23.6 ± 9.1 mg/100 g/min in the sitting position. The changes were not statistically significant. None of the patients developed clinical cerebral vasospasm. Changing HOB position in the setting of SAH did not significantly affect cerebral or regional blood flow. These data suggest that early mobilization should be considered given the detrimental effects of prolonged bed rest. David K. Kung, Nohra Chalouhi, Pascal M. Jabbour, Robert M. Starke, Aaron S. Dumont, H. Richard Winn, Matthew A. Howard III, and David M. Hasan Copyright © 2013 David K. Kung et al. All rights reserved.