BioMed Research International: Neuroscience The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Neuroprotective Effects of Clostridium butyricum against Vascular Dementia in Mice via Metabolic Butyrate Wed, 07 Oct 2015 14:00:10 +0000 Probiotics actively participate in neuropsychiatric disorders. However, the role of gut microbiota in brain disorders and vascular dementia (VaD) remains unclear. We used a mouse model of VaD induced by a permanent right unilateral common carotid arteries occlusion (rUCCAO) to investigate the neuroprotective effects and possible underlying mechanisms of Clostridium butyricum. Following rUCCAO, C. butyricum was intragastrically administered for 6 successive weeks. Cognitive function was estimated. Morphological examination was performed by electron microscopy and hematoxylin-eosin (H&E) staining. The BDNF-PI3K/Akt pathway-related proteins were assessed by western blot and immunohistochemistry. The diversity of gut microbiota and the levels of butyrate in the feces and the brains were determined. The results showed that C. butyricum significantly attenuated the cognitive dysfunction and histopathological changes in VaD mice. C. butyricum not only increased the levels of BDNF and Bcl-2 and decreased level of Bax but also induced Akt phosphorylation (p-Akt) and ultimately reduced neuronal apoptosis. Moreover, C. butyricum could regulate the gut microbiota and restore the butyrate content in the feces and the brains. These results suggest that C. butyricum might be effective in the treatment of VaD by regulating the gut-brain axis and that it can be considered a new therapeutic strategy against VaD. Jiaming Liu, Jing Sun, Fangyan Wang, Xichong Yu, Zongxin Ling, Haixiao Li, Huiqing Zhang, Jiangtao Jin, Wenqian Chen, Mengqi Pang, Junjie Yu, Yiwen He, and Jiru Xu Copyright © 2015 Jiaming Liu et al. All rights reserved. Coagulation Parameters and Risk of Progressive Hemorrhagic Injury after Traumatic Brain Injury: A Systematic Review and Meta-Analysis Thu, 17 Sep 2015 11:34:11 +0000 Intracranial hemorrhage (ICH) after traumatic brain injury (TBI) commonly increases in size and coagulopathy has been implicated in such progression. Our aim is to perform a meta-analysis to assess their relationship. Cochrane library, PubMed, and EMBASE were searched for literatures. Pooled effect sizes and 95% confidential intervals (CIs) were calculated using random-effects model. We included six studies, involving 1700 participants with 540 progressive hemorrhagic injuries (PHIs). Our findings indicate that PT, D-dimer level, and INR value are positively associated with the risk of PHI. Higher level of PLT and Fg seemed to suggest a lower risk of PHI. Among these parameters, higher D-dimer level and INR value would possess more powerful strength in predicting PHI. Danfeng Zhang, Shun Gong, Hai Jin, Junyu Wang, Ping Sheng, Wei Zou, Yan Dong, and Lijun Hou Copyright © 2015 Danfeng Zhang et al. All rights reserved. Biomarkers of Brain Function and Injury: Biological and Clinical Significance Wed, 02 Sep 2015 05:47:00 +0000 Diego Gazzolo, Giovanni Li Volti, Antonio W. D. Gavilanes, and Giovanni Scapagnini Copyright © 2015 Diego Gazzolo et al. All rights reserved. Biomarkers of Brain Damage: S100B and NSE Concentrations in Cerebrospinal Fluid—A Normative Study Tue, 01 Sep 2015 13:31:04 +0000 NSE and S100B belong among the so-called structural proteins of the central nervous system (CNS). Lately, this group of structural proteins has been profusely used as specific biomarkers of CNS tissue damage. So far, the majority of the research papers have focused predominantly on the concentrations of these proteins in blood in relation to CNS damage of various origins. Considering the close anatomic and functional relationship between the brain or spinal cord and cerebrospinal fluid (CSF), in case of a CNS injury, a rapid and pronounced increase of the concentrations of structural proteins specifically in CSF takes place. This study inquires into the physiological concentrations of NSE and S100B proteins in CSF, carried out on a sufficiently large group of 601 patients. The detected values can be used for determination of a normal reference range in CSF in a clinical laboratory diagnostics. Lenka Hajduková, Ondřej Sobek, Darina Prchalová, Zuzana Bílková, Martina Koudelková, Jiřina Lukášková, and Inka Matuchová Copyright © 2015 Lenka Hajduková et al. All rights reserved. Expression Signatures of Long Noncoding RNAs in Adolescent Idiopathic Scoliosis Tue, 01 Sep 2015 12:33:36 +0000 Purpose. Adolescent idiopathic scoliosis (AIS), the most common pediatric spinal deformity, is considered a complex genetic disease. Causing genes and pathogenesis of AIS are still unclear. This study was designed to identify differentially expressed long noncoding RNAs (lncRNAs) involving the pathogenesis of AIS. Methods. We first performed comprehensive screening of lncRNA and mRNA in AIS patients and healthy children using Agilent human lncRNA + mRNA Array V3.0 microarray. LncRNAs expression in different AIS patients was further evaluated using quantitative PCR. Results. A total of 139 lncRNAs and 546 mRNAs were differentially expressed between AIS patients and healthy control. GO and Pathway analysis showed that these mRNAs might be involved in bone mineralization, neuromuscular junction, skeletal system morphogenesis, nucleotide and nucleic acid metabolism, and regulation of signal pathway. Four lncRNAs (ENST00000440778.1, ENST00000602322.1, ENST00000414894.1, and TCONS_00028768) were differentially expressed between different patients when grouped according to age, height, classification, severity of scoliosis, and Risser grade. Conclusions. This study demonstrates the abnormal expression of lncRNAs and mRNAs in AIS, and the expression of some lncRNAs was related to clinical features. This study is helpful for further understanding of lncRNAs in pathogenesis, treatment, and prognosis of AIS. Xiao-Yang Liu, Liang Wang, Bin Yu, Qian-yu Zhuang, and Yi-Peng Wang Copyright © 2015 Xiao-Yang Liu et al. All rights reserved. Molecular Biomarkers for Embryonic and Adult Neural Stem Cell and Neurogenesis Tue, 01 Sep 2015 07:45:15 +0000 The procedure of neurogenesis has made numerous achievements in the past decades, during which various molecular biomarkers have been emerging and have been broadly utilized for the investigation of embryonic and adult neural stem cell (NSC). Nevertheless, there is not a consistent and systematic illustration to depict the functional characteristics of the specific markers expressed in distinct cell types during the different stages of neurogenesis. Here we gathered and generalized a series of NSC biomarkers emerging during the procedures of embryonic and adult neural stem cell, which may be used to identify the subpopulation cells with distinguishing characters in different timeframes of neurogenesis. The identifications of cell patterns will provide applications to the detailed investigations of diverse developmental cell stages and the extents of cell differentiation, which will facilitate the tracing of cell time-course and fate determination of specific cell types and promote the further and literal discoveries of embryonic and adult neurogenesis. Meanwhile, via the utilization of comprehensive applications under the aiding of the systematic knowledge framework, researchers may broaden their insights into the derivation and establishment of novel technologies to analyze the more detailed process of embryogenesis and adult neurogenesis. Juan Zhang and Jianwei Jiao Copyright © 2015 Juan Zhang and Jianwei Jiao. All rights reserved. Gray and White Matter Volumes and Cognitive Dysfunction in Drug-Naïve Newly Diagnosed Pediatric Epilepsy Mon, 31 Aug 2015 13:36:35 +0000 Epilepsy patients often have cognitive dysfunction even at early stages of disease. We investigated the relationship between structural findings and neuropsychological status in drug-naïve newly diagnosed pediatric epilepsy patients. Thirty newly diagnosed pediatric epilepsy patients and 25 healthy control subjects aged 7~16 years were enrolled, who were assessed by the Korean version of the Wechsler Intelligence Scale for Children (K-WISC-III), the Stroop test, and the trail making test (TMT). Optimized voxel-based morphometry (VBM) was performed for both Gray Matter (GM) and White Matter (WM) volumes. Lower performance levels of verbal intelligence quotient, freedom from distractibility, and executive function were observed in epilepsy group. Interestingly, poor performance in these cognitive subdomains was correlated with regional VBM findings involving both GM and WM volumes, but with different patterns between groups. GM volumes revealed clear differences predominantly in the bilateral frontal regions. These findings indicate that certain cognitive functions may be affected in the early stage of epilepsy, not related to the long-standing epilepsy or medication, but more related to the neurocognitive developmental process in this age. Epilepsy can lead to neuroanatomical alterations in both GM and WM, which may affect cognitive functions, during early stages even before commencement of AED medication. Jung Hwa Lee, Song E. Kim, Chang-hyun Park, Jeong Hyun Yoo, and Hyang Woon Lee Copyright © 2015 Jung Hwa Lee et al. All rights reserved. The Cortisol Awakening Response in Patients with Poststroke Depression Is Blunted and Negatively Correlated with Depressive Mood Mon, 31 Aug 2015 13:17:13 +0000 It is important to reduce poststroke depression (PSD) to improve the stroke outcomes and quality of life in stroke patients, but the underlying mechanisms of PSD are not completely understood. As many studies implicate dysregulation of hypothalamic-pituitary-adrenal axis in the etiology of major depression and stroke, we compared the cortisol awakening response (CAR) of 28 admitted PSD patients with that of 23 age-matched caregiver controls. Saliva samples for cortisol measurement were collected immediately, 15, 30, and 45 min after awakening for two consecutive days. Depressive mood status in PSD patients was determined with Beck Depression Inventory and Hamilton Depression Rating Scale. Salivary cortisol levels of PSD patients did not rise significantly at any sampling time, showing a somewhat flat curve. Caregiver controls showed significantly higher CAR at 15 and 30 min after awakening compared to PSD patients even though the two groups did not differ at awakening or 45 min after awakening. Area-under-the-curve analysis revealed a significant negative correlation between the CAR and the degree of depression in PSD patients. Thus, our findings suggest that poststroke depression is closely related with dysfunctional HPA axis indicated by blunted CAR. Oh Jeong Kwon, Munsoo Kim, Ho Sub Lee, Kang-keyng Sung, and Sangkwan Lee Copyright © 2015 Oh Jeong Kwon et al. All rights reserved. Biomarkers of Brain Damage and Postoperative Cognitive Disorders in Orthopedic Patients: An Update Mon, 31 Aug 2015 12:43:38 +0000 The incidence of postoperative cognitive dysfunction (POCD) in orthopedic patients varies from 16% to 45%, although it can be as high as 72%. As a consequence, the hospitalization time of patients who developed POCD was longer, the outcome and quality of life were worsened, and prolonged medical and social assistance were necessary. In this review the short description of such biomarkers of brain damage as the S100B protein, NSE, GFAP, Tau protein, metalloproteinases, ubiquitin C terminal hydrolase, microtubule-associated protein, myelin basic protein, α-II spectrin breakdown products, and microRNA was made. The role of thromboembolic material in the development of cognitive decline was also discussed. Special attention was paid to optimization of surgical and anesthetic procedures in the prevention of postoperative cognitive decline. Dariusz Tomaszewski Copyright © 2015 Dariusz Tomaszewski. All rights reserved. Circulating S100B and Adiponectin in Children Who Underwent Open Heart Surgery and Cardiopulmonary Bypass Mon, 31 Aug 2015 11:35:03 +0000 Background. S100B protein, previously proposed as a consolidated marker of brain damage in congenital heart disease (CHD) newborns who underwent cardiac surgery and cardiopulmonary bypass (CPB), has been progressively abandoned due to S100B CNS extra-source such as adipose tissue. The present study investigated CHD newborns, if adipose tissue contributes significantly to S100B serum levels. Methods. We conducted a prospective study in 26 CHD infants, without preexisting neurological disorders, who underwent cardiac surgery and CPB in whom blood samples for S100B and adiponectin (ADN) measurement were drawn at five perioperative time-points. Results. S100B showed a significant increase from hospital admission up to 24 h after procedure reaching its maximum peak during CPB and at the end of the surgical procedure. Moreover, ADN showed a flat pattern and no significant differences have been found all along perioperative monitoring. ADN/S100B ratio pattern was identical to S100B alone with the higher peak at the end of CPB and remained higher up to 24 h from surgery. Conclusions. The present study provides evidence that, in CHD infants, S100B protein is not affected by an extra-source adipose tissue release as suggested by no changes in circulating ADN concentrations. Alessandro Varrica, Angela Satriano, Alessandro Frigiola, Alessandro Giamberti, Guido Tettamanti, Luigi Anastasia, Erika Conforti, Antonio D. W. Gavilanes, Luc J. Zimmermann, Hans J. S. Vles, Giovanni Li Volti, and Diego Gazzolo Copyright © 2015 Alessandro Varrica et al. All rights reserved. Regeneration, Plasticity, and Induced Molecular Programs in Adult Zebrafish Brain Mon, 31 Aug 2015 11:32:51 +0000 Regenerative capacity of the brain is a variable trait within animals. Aquatic vertebrates such as zebrafish have widespread ability to renew their brains upon damage, while mammals have—if not none—very limited overall regenerative competence. Underlying cause of such a disparity is not fully evident; however, one of the reasons could be activation of peculiar molecular programs, which might have specific roles after injury or damage, by the organisms that regenerate. If this hypothesis is correct, then there must be genes and pathways that (a) are expressed only after injury or damage in tissues, (b) are biologically and functionally relevant to restoration of neural tissue, and (c) are not detected in regenerating organisms. Presence of such programs might circumvent the initial detrimental effects of the damage and subsequently set up the stage for tissue redevelopment to take place by modulating the plasticity of the neural stem/progenitor cells. Additionally, if transferable, those “molecular mechanisms of regeneration” could open up new avenues for regenerative therapies of humans in clinical settings. This review focuses on the recent studies addressing injury/damage-induced molecular programs in zebrafish brain, underscoring the possibility of the presence of genes that could be used as biomarkers of neural plasticity and regeneration. Mehmet Ilyas Cosacak, Christos Papadimitriou, and Caghan Kizil Copyright © 2015 Mehmet Ilyas Cosacak et al. All rights reserved. Posterior Cingulate Lactate as a Metabolic Biomarker in Amnestic Mild Cognitive Impairment Mon, 31 Aug 2015 11:30:18 +0000 Mitochondrial dysfunction represents a central factor within the pathogenesis of the Alzheimer’s disease (AD) spectrum. We hypothesized that in vivo measurements of lactate (lac), a by-product of glycolysis, would correlate with functional impairment and measures of brain health in a cohort of 15 amnestic mild cognitive impairment (aMCI) individuals. Lac was quantified from the precuneus/posterior cingulate (PPC) using 2-dimensional J-resolved magnetic resonance spectroscopy (MRS). Additionally, standard behavioral and imaging markers of aMCI disease progression were acquired. PPC lac was negatively correlated with performance on the Wechsler logical memory tests and on the minimental state examination even after accounting for gray matter, cerebral spinal fluid volume, and age. No such relationships were observed between lac and performance on nonmemory tests. Significant negative relationships were also noted between PPC lac and hippocampal volume and PPC functional connectivity. Together, these results reveal that aMCI individuals with a greater disease progression have increased concentrations of PPC lac. Because lac is upregulated as a compensatory response to mitochondrial impairment, we propose that J-resolved MRS of lac is a noninvasive, surrogate biomarker of impaired metabolic function and would provide a useful means of tracking mitochondrial function during therapeutic trials targeting brain metabolism. Kurt E. Weaver, Todd L. Richards, Rebecca G. Logsdon, Ellen L. McGough, Satoshi Minoshima, Elizabeth H. Aylward, Natalia M. Kleinhans, Thomas J. Grabowski, Susan M. McCurry, and Linda Teri Copyright © 2015 Kurt E. Weaver et al. All rights reserved. Role and Importance of IGF-1 in Traumatic Brain Injuries Mon, 31 Aug 2015 10:52:09 +0000 It is increasingly affirmed that most of the long-term consequences of TBI are due to molecular and cellular changes occurring during the acute phase of the injury and which may, afterwards, persist or progress. Understanding how to prevent secondary damage and improve outcome in trauma patients, has been always a target of scientific interest. Plans of studies focused their attention on the posttraumatic neuroendocrine dysfunction in order to achieve a correlation between hormone blood level and TBI outcomes. The somatotropic axis (GH and IGF-1) seems to be the most affected, with different alterations between the acute and late phases. IGF-1 plays an important role in brain growth and development, and it is related to repair responses to damage for both the central and peripheral nervous system. The IGF-1 blood levels result prone to decrease during both the early and late phases after TBI. Despite this, experimental studies on animals have shown that the CNS responds to the injury upregulating the expression of IGF-1; thus it appears to be related to the secondary mechanisms of response to posttraumatic damage. We review the mechanisms involving IGF-1 in TBI, analyzing how its expression and metabolism may affect prognosis and outcome in head trauma patients. Annunziato Mangiola, Vera Vigo, Carmelo Anile, Pasquale De Bonis, Giammaria Marziali, and Giorgio Lofrese Copyright © 2015 Annunziato Mangiola et al. All rights reserved. Intra-Amniotic LPS Induced Region-Specific Changes in Presynaptic Bouton Densities in the Ovine Fetal Brain Mon, 31 Aug 2015 10:01:31 +0000 Rationale. Chorioamnionitis has been associated with increased risk for fetal brain damage. Although, it is now accepted that synaptic dysfunction might be responsible for functional deficits, synaptic densities/numbers after a fetal inflammatory challenge have not been studied in different regions yet. Therefore, we tested in this study the hypothesis that LPS-induced chorioamnionitis caused profound changes in synaptic densities in different regions of the fetal sheep brain. Material and Methods. Chorioamnionitis was induced by a 10 mg intra-amniotic LPS injection at two different exposure intervals. The fetal brain was studied at 125 days of gestation (term = 150 days) either 2 (LPS2D group) or 14 days (LPS14D group) after LPS or saline injection (control group). Synaptophysin immunohistochemistry was used to quantify the presynaptic density in layers 2-3 and 5-6 of the motor cortex, somatosensory cortex, entorhinal cortex, and piriforme cortex, in the nucleus caudatus and putamen and in CA1/2, CA3, and dentate gyrus of the hippocampus. Results. There was a significant reduction in presynaptic bouton densities in layers 2-3 and 5-6 of the motor cortex and in layers 2-3 of the entorhinal and the somatosensory cortex, in the nucleus caudate and putamen and the CA1/2 and CA3 of the hippocampus in the LPS2D compared to control animals. Only in the motor cortex and putamen, the presynaptic density was significantly decreased in the LPS14 D compared to the control group. No changes were found in the dentate gyrus of the hippocampus and the piriforme cortex. Conclusion. We demonstrated that LPS-induced chorioamnionitis caused a decreased density in presynaptic boutons in different areas in the fetal brain. These synaptic changes seemed to be region-specific, with some regions being more affected than others, and seemed to be transient in some regions. Eveline Strackx, Reint K. Jellema, Rebecca Rieke, Ruth Gussenhoven, Johan S. H. Vles, Boris W. Kramer, and Antonio W. D. Gavilanes Copyright © 2015 Eveline Strackx et al. All rights reserved. Sustained Reduction of Cerebellar Activity in Experimental Epilepsy Mon, 31 Aug 2015 09:44:45 +0000 Clinical and experimental evidence suggests a role for the cerebellum in seizure control, while no data are available on cerebellar activity between seizures. We hypothesized that interictal regional activity of the deep cerebellar nuclei is reduced in epilepsy and tested this in an animal model by using ΔFosB and cytochrome oxidase (COX) (immuno)histochemistry. The expression of these two markers of neuronal activity was analysed in the dentate nucleus (DN), interpositus nucleus (IN), and fastigial nucleus (FN) of the cerebellum of fully amygdala kindled rats that were sacrificed 48 hours after their last seizure. The DN and FN of kindled rats exhibited 25 to 29% less ΔFosB immunopositive cells than their respective counterpart in sham controls (). COX expression in the DN and FN of kindled animals was reduced by 32 to 33% compared to respective control values (). These results indicate that an epileptogenic state is characterized by decreased activity of deep cerebellar nuclei, especially the DN and FN. Possible consequences may include a decreased activation of the thalamus, contributing to further seizure spread. Restoration of FN activity by low frequency electrical stimulation is suggested as a possible treatment option in chronic epilepsy. Kim Rijkers, Véronique M. P. Moers-Hornikx, Roelof J. Hemmes, Marlien W. Aalbers, Yasin Temel, Johan S. H. Vles, and Govert Hoogland Copyright © 2015 Kim Rijkers et al. All rights reserved. Epitope Fingerprinting for Recognition of the Polyclonal Serum Autoantibodies of Alzheimer’s Disease Mon, 31 Aug 2015 09:24:07 +0000 Autoantibodies (aAb) associated with Alzheimer’s disease (AD) have not been sufficiently characterized and their exact involvement is undefined. The use of information technology and computerized analysis with phage display technology was used, in the present research, to map the epitope of putative self-antigens in AD patients. A 12-mer random peptide library, displayed on M13 phages, was screened using IgG from AD patients with two repetitions. Seventy-one peptides were isolated; however, only 10 were positive using the Elisa assay technique (Elisa Index > 1). The results showed that the epitope regions of the immunoreactive peptides, identified by phage display analysis, were on the exposed surfaces of the proteins. The putative antigens MAST1, Enah, MAO-A, X11/MINT1, HGF, SNX14, ARHGAP 11A, APC, and CENTG3, which have been associated with AD or have functions in neural tissue, may indicate possible therapeutic targets. Luiz Carlos de Oliveira-Júnior, Fabiana de Almeida Araújo Santos, Luiz Ricardo Goulart, and Carlos Ueira-Vieira Copyright © 2015 Luiz Carlos de Oliveira-Júnior et al. All rights reserved. Endogenous Two-Photon Excited Fluorescence Provides Label-Free Visualization of the Inflammatory Response in the Rodent Spinal Cord Tue, 18 Aug 2015 11:37:03 +0000 Activation of CNS resident microglia and invasion of external macrophages plays a central role in spinal cord injuries and diseases. Multiphoton microscopy based on intrinsic tissue properties offers the possibility of label-free imaging and has the potential to be applied in vivo. In this work, we analyzed cellular structures displaying endogenous two-photon excited fluorescence (TPEF) in the pathologic spinal cord. It was compared qualitatively and quantitatively to Iba1 and CD68 immunohistochemical staining in two models: rat spinal cord injury and mouse encephalomyelitis. The extent of tissue damage was retrieved by coherent anti-Stokes Raman scattering (CARS) and second harmonic generation imaging. The pattern of CD68-positive cells representing postinjury activated microglia/macrophages was colocalized to the TPEF signal. Iba1-positive microglia were found in areas lacking any TPEF signal. In peripheral areas of inflammation, we found similar numbers of CD68-positive microglia/macrophages and TPEF-positive structures while the number of Iba1-positive cells was significantly higher. Therefore, we conclude that multiphoton imaging of unstained spinal cord tissue enables retrieving the extent of microglia activation by acquisition of endogenous TPEF. Future application of this technique in vivo will enable monitoring inflammatory responses of the nervous system allowing new insights into degenerative and regenerative processes. Ortrud Uckermann, Roberta Galli, Rudolf Beiermeister, Kerim-Hakan Sitoci-Ficici, Robert Later, Elke Leipnitz, Ales Neuwirth, Triantafyllos Chavakis, Edmund Koch, Gabriele Schackert, Gerald Steiner, and Matthias Kirsch Copyright © 2015 Ortrud Uckermann et al. All rights reserved. Motor Neuron Diseases in Sub-Saharan Africa: The Need for More Population-Based Studies Wed, 12 Aug 2015 08:18:36 +0000 Motor neuron diseases (MNDs) are devastating neurological diseases that are characterised by gradual degeneration and death of motor neurons. Major types of MNDs include amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). These diseases are incurable, with limited disease-modifying treatment options. In order to improve MND-based biomedical research, drug development, and clinical care, population-based studies will be important. These studies, especially among less-studied populations, might identify novel factors controlling disease susceptibility and resistance. To evaluate progress in MND research in Africa, we examined the published literature on MNDs in Sub-Saharan Africa to identify disease prevalence, genetic factors, and other risk factors. Our findings indicate that the amount of research evidence on MNDs in Sub-Saharan Africa is scanty; molecular and genetics-based studies are particularly lacking. While only a few genetic studies were identified, these studies strongly suggest that there appear to be population-specific causes of MNDs among Africans. MND genetic underpinnings vary among different African populations and also between African and non-African populations. Further studies, especially molecular, genetic and genomic studies, will be required to advance our understanding of MND biology among African populations. Insights from these studies would help to improve the timeliness and accuracy of clinical diagnosis and treatment. Emmanuel Quansah and Thomas K. Karikari Copyright © 2015 Emmanuel Quansah and Thomas K. Karikari. All rights reserved. Neuroinflammation and Neurodegeneration: Pinpointing Pathological and Pharmacological Targets Thu, 30 Jul 2015 07:56:23 +0000 Antonio Carlos Pinheiro de Oliveira, Eduardo Candelario-Jalil, Bernd L. Fiebich, Magda da Silva Santos, András Palotás, and Helton José dos Reis Copyright © 2015 Antonio Carlos Pinheiro de Oliveira et al. All rights reserved. Cocaine Causes Apoptotic Death in Rat Mesencephalon and Striatum Primary Cultures Wed, 29 Jul 2015 13:16:23 +0000 To study cocaine’s toxic effects in vitro, we have used primary mesencephalic and striatal cultures from rat embryonic brain. Treatment with cocaine causes a dramatic increase in DNA fragmentation in both primary cultures. The toxicity induced by cocaine was paralleled with a concomitant decrease in the microtubule associated protein 2 (MAP2) and/or neuronal nucleus protein (NeuN) staining. We also observed in both cultures that the cell death caused by cocaine was induced by an apoptotic mechanism, confirmed by TUNEL assay. Therefore, the present paper shows that cocaine causes apoptotic cell death and inhibition of the neurite prolongation in striatal and mesencephalic cell culture. These data suggest that if similar neuronal damage could be produced in the developing human brain, it could account for the qualitative or quantitative defects in neuronal pathways that cause a major handicap in brain function following prenatal exposure to cocaine. Lucilia B. Lepsch, Cleopatra S. Planeta, and Critoforo Scavone Copyright © 2015 Lucilia B. Lepsch et al. All rights reserved. Intellectual Impairment in Patients with Newly Diagnosed HIV Infection in Southwestern Nigeria Wed, 29 Jul 2015 09:22:38 +0000 Neurocognitive impairment is a detrimental complication of HIV infection. Here, we characterized the intellectual performance of patients with newly diagnosed HIV infection in southwestern Nigeria. We conducted a prospective study at Owo Federal Medical Center by using the adapted Wechsler Adult Intelligence Scale (WAIS). The raw scores were converted to standardized scores (z-scores) and correlated with clinical and laboratory findings. Fifty-eight HIV positive patients were recruited; 72% were in WHO stages 3 and 4. We detected a high rate of intellectual impairment in HIV positive patients and controls (63.8% and 10%, resp.; ). HIV positive patients performed worse throughout the subtests of both verbal and performance intelligence quotients. Presence of opportunistic infections was associated with worse performance in the similarities and digit symbol tests and performance and full scale scores. Lower body weight correlated with poor performance in different WAIS subtests. The high rate of advanced disease stage warrants measures aimed at earlier diagnosis and treatment. Assessment of neurocognitive performance at diagnosis may offer the opportunity to improve functioning in daily life and counteract disease progression. Taofiki A. Sunmonu, Johann Sellner, Olubunmi A. Ogunrin, Frank A. Imarhiagbe, Morenikeji A. Komolafe, Olusegun T. Afolabi, Olayinka S. Ilesanmi, Fatai Olanrewaju, and Benedicta Y. Oladimeji Copyright © 2015 Taofiki A. Sunmonu et al. All rights reserved. S100B Inhibitor Pentamidine Attenuates Reactive Gliosis and Reduces Neuronal Loss in a Mouse Model of Alzheimer’s Disease Wed, 29 Jul 2015 08:48:37 +0000 Among the different signaling molecules released during reactive gliosis occurring in Alzheimer’s disease (AD), the astrocyte-derived S100B protein plays a key role in neuroinflammation, one of the hallmarks of the disease. The use of pharmacological tools targeting S100B may be crucial to embank its effects and some of the pathological features of AD. The antiprotozoal drug pentamidine is a good candidate since it directly blocks S100B activity by inhibiting its interaction with the tumor suppressor p53. We used a mouse model of amyloid beta- (Aβ-) induced AD, which is characterized by reactive gliosis and neuroinflammation in the brain, and we evaluated the effect of pentamidine on the main S100B-mediated events. Pentamidine caused the reduction of glial fibrillary acidic protein, S100B, and RAGE protein expression, which are signs of reactive gliosis, and induced p53 expression in astrocytes. Pentamidine also reduced the expression of proinflammatory mediators and markers, thus reducing neuroinflammation in AD brain. In parallel, we observed a significant neuroprotection exerted by pentamidine on CA1 pyramidal neurons. We demonstrated that pentamidine inhibits Aβ-induced gliosis and neuroinflammation in an animal model of AD, thus playing a role in slowing down the course of the disease. Carla Cirillo, Elena Capoccia, Teresa Iuvone, Rosario Cuomo, Giovanni Sarnelli, Luca Steardo, and Giuseppe Esposito Copyright © 2015 Carla Cirillo et al. All rights reserved. An Overview of Potential Targets for Treating Amyotrophic Lateral Sclerosis and Huntington’s Disease Wed, 29 Jul 2015 08:05:16 +0000 Neurodegenerative diseases affect millions of people worldwide. Progressive damage or loss of neurons, neurodegeneration, has severe consequences on the mental and physical health of a patient. Despite all efforts by scientific community, there is currently no cure or manner to slow degeneration progression. We review some treatments that attempt to prevent the progress of some of major neurodegenerative diseases: Amyotrophic Lateral Sclerosis and Huntington’s disease. Caroline Zocatelli de Paula, Bruno Daniel Correia Gonçalves, and Luciene Bruno Vieira Copyright © 2015 Caroline Zocatelli de Paula et al. All rights reserved. Multicontrast MRI Quantification of Focal Inflammation and Degeneration in Multiple Sclerosis Wed, 29 Jul 2015 07:24:56 +0000 Introduction. Local microstructural pathology in multiple sclerosis patients might influence their clinical performance. This study applied multicontrast MRI to quantify inflammation and neurodegeneration in MS lesions. We explored the impact of MRI-based lesion pathology in cognition and disability. Methods. 36 relapsing-remitting MS subjects and 18 healthy controls underwent neurological, cognitive, behavioural examinations and 3 T MRI including (i) fluid attenuated inversion recovery, double inversion recovery, and magnetization-prepared gradient echo for lesion count; (ii) T1, T2, and T2* relaxometry and magnetisation transfer imaging for lesion tissue characterization. Lesions were classified according to the extent of inflammation/neurodegeneration. A generalized linear model assessed the contribution of lesion groups to clinical performances. Results. Four lesion groups were identified and characterized by (1) absence of significant alterations, (2) prevalent inflammation, (3) concomitant inflammation and microdegeneration, and (4) prevalent tissue loss. Groups 1, 3, 4 correlated with general disability (Adj-; ), executive function (Adj-; ), verbal memory (Adj-; ), and attention (Adj-; ). Conclusion. Multicontrast MRI provides a new approach to infer in vivo histopathology of plaques. Our results support evidence that neurodegeneration is the major determinant of patients’ disability and cognitive dysfunction. Guillaume Bonnier, Alexis Roche, David Romascano, Samanta Simioni, Djalel Eddine Meskaldji, David Rotzinger, Ying-Chia Lin, Gloria Menegaz, Myriam Schluep, Renaud Du Pasquier, Tilman Johannes Sumpf, Jens Frahm, Jean-Philippe Thiran, Gunnar Krueger, and Cristina Granziera Copyright © 2015 Guillaume Bonnier et al. All rights reserved. CCL27: Novel Cytokine with Potential Role in Pathogenesis of Multiple Sclerosis Wed, 29 Jul 2015 07:00:39 +0000 Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease of unknown etiology. Leukocyte infiltration of brain tissue and the subsequent inflammation, demyelination, axonal damage, and formation of sclerotic plaques is a hallmark of MS. Upregulation of proinflammatory cytokines has been suggested to play an essential role in regulating lymphocyte migration in MS. Here we present data on serum cytokine expression in MS cases. Increased serum levels of IL-17 and IL-23 were observed, suggesting activation of the Th17 population of immune effector cells. Additionally, increased levels of IL-22 were observed in the serum of those with acute phase MS. Unexpectedly, we observed an upregulation of the serum chemokine CCL27 in newly diagnosed and acute MS cases. CCL27 is an inflammatory chemokine associated with homing of memory T cells to sites of inflammation. Therefore, its upregulation in association with MS suggests a potential role in disease pathogenesis. Our data supports previous reports showing IL-17 and -23 upregulation in association with MS and potentially identify a previously unknown involvement for CCL27. Svetlana F. Khaiboullina, Aigul R. Gumerova, Irina F. Khafizova, Ekaterina V. Martynova, Vincent C. Lombardi, Saverio Bellusci, and Albert A. Rizvanov Copyright © 2015 Svetlana F. Khaiboullina et al. All rights reserved. Insights into Neuroinflammation in Parkinson’s Disease: From Biomarkers to Anti-Inflammatory Based Therapies Wed, 29 Jul 2015 06:48:16 +0000 Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide, being characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Among several putative factors that may contribute to PD pathogenesis, inflammatory mechanisms may play a pivotal role. The involvement of microglial activation as well as of brain and peripheral immune mediators in PD pathophysiology has been reported by clinical and experimental studies. These inflammatory biomarkers evaluated by imaging techniques and/or by biological sample analysis have become valuable tools for PD diagnosis and prognosis. Regardless of the significant increase in the number of people suffering from PD, there are still no established disease-modifying or neuroprotective therapies for it. There is growing evidence of protective effect of anti-inflammatory drugs on PD development. Herein, we reviewed the current literature regarding the central nervous system and peripheral immune biomarkers in PD and advances in diagnostic and prognostic tools as well as the neuroprotective effects of anti-inflammatory therapies. Natália Pessoa Rocha, Aline Silva de Miranda, and Antônio Lúcio Teixeira Copyright © 2015 Natália Pessoa Rocha et al. All rights reserved. Oligoclonal Bands in Cerebrospinal Fluid of Black Patients with Multiple Sclerosis Wed, 29 Jul 2015 06:48:02 +0000 Genetic susceptibility is a well-recognized factor in the onset of multiple sclerosis (MS). The objective of this study was to determine the frequency of oligoclonal bands (OCB) restricted to the cerebrospinal fluid, in an ethnically mixed group of MS patients in the city of São Paulo, Brazil. Techniques used to detect OCB consisted of isoelectric focusing followed by immunoblotting. OCB were found in 49 (54.4%) out of 90 patients with clinically definite MS; out of the 23 brown/black patients, 17 (73.9%) were OCB+; out of the 66 white patients, 32 (48.5%) were OCB+; and the only patient yellow was OCB+ (). Analysis of the IgG index was also consistent with the findings, but with lower statistical significance. The data presented in our study show that the ethnic differences in MS extend to the immune response. Paulo Diniz da Gama, Luís dos Ramos Machado, José Antonio Livramento, Hélio Rodrigues Gomes, Tarso Adoni, Rogério de Rizo Morales, Rodrigo Assad Diniz da Gama, Daniel Assad Diniz da Gama, Marco Aurélio Lana-Peixoto, Yara Dadalti Fragoso, and Dagoberto Callegaro Copyright © 2015 Paulo Diniz da Gama et al. All rights reserved. Transdermal Nicotine Application Attenuates Cardiac Dysfunction after Severe Thermal Injury Tue, 28 Jul 2015 14:17:23 +0000 Background. Severe burn trauma leads to an immediate and strong inflammatory response inciting cardiac dysfunction that is associated with high morbidity and mortality. The aim of this study was to determine whether transdermal application of nicotine could influence the burn-induced cardiac dysfunction via its known immunomodulatory effects. Material and Methods. A standardized rat burn model was used in 35 male Sprague Dawley rats. The experimental animals were divided into a control group, a burn trauma group, a burn trauma group with additional nicotine treatment, and a sham group with five experimental animals per group. The latter two groups received nicotine administration. Using microtip catheterization, functional parameters of the heart were assessed 12 or 24 hours after infliction of burn trauma. Results. Burn trauma led to significantly decreased blood pressure (BP) values whereas nicotine administration normalized BP. As expected, burn trauma also induced a significant deterioration of myocardial contractility and relaxation parameters. After application of nicotine these adverse effects were attenuated. Conclusion. The present study showed that transdermal nicotine administration has normalizing effects on burn-induced myocardial dysfunction parameters. Further research is warranted to gain insight in molecular mechanisms and pathways and to evaluate potential treatment options in humans. Leif Claassen, Stephan Papst, Kerstin Reimers, Christina Stukenborg-Colsman, Lars Steinstraesser, Peter M. Vogt, Theresia Kraft, and Andreas D. Niederbichler Copyright © 2015 Leif Claassen et al. All rights reserved. Peripheral Administration of Tumor Necrosis Factor-Alpha Induces Neuroinflammation and Sickness but Not Depressive-Like Behavior in Mice Tue, 28 Jul 2015 14:09:11 +0000 Clinical observations indicate that activation of the TNF-α system may contribute to the development of inflammation-associated depression. Here, we tested the hypothesis that systemic upregulation of TNF-α induces neuroinflammation and behavioral changes relevant to depression. We report that a single intraperitoneal injection of TNF-α in mice increased serum and brain levels of the proinflammatory mediators TNF-α, IL-6, and MCP-1, in a dose- and time-dependent manner, but not IL-1β. Protein levels of the anti-inflammatory cytokine IL-10 increased in serum but not in the brain. The transient release of immune molecules was followed by glial cell activation as indicated by increased astrocyte activation in bioluminescent Gfap-luc mice and elevated immunoreactivity against the microglial marker Iba1 in the dentate gyrus of TNF-α-challenged mice. Additionally, TNF-α-injected mice were evaluated in a panel of behavioral tests commonly used to study sickness and depressive-like behavior in rodents. Our behavioral data imply that systemic administration of TNF-α induces a strong sickness response characterized by reduced locomotor activity, decreased fluid intake, and body weight loss. Depressive-like behavior could not be separated from sickness at any of the time points studied. Together, these results demonstrate that peripheral TNF-α affects the central nervous system at a neuroimmune and behavioral level. Steven Biesmans, Jan A. Bouwknecht, Luc Ver Donck, Xavier Langlois, Paul D. Acton, Patrick De Haes, Nima Davoodi, Theo F. Meert, Niels Hellings, and Rony Nuydens Copyright © 2015 Steven Biesmans et al. All rights reserved. Environmental Enrichment Attenuated Sevoflurane-Induced Neurotoxicity through the PPAR-γ Signaling Pathway Mon, 06 Jul 2015 11:10:31 +0000 Sevoflurane is the most widely used inhaled anesthetic. Environmental enrichment (EE) can reverse sevoflurane-induced learning and memory impairment in young mice. However, the mechanism by which EE elicits this effect is unclear. The peroxisome proliferator-activated receptor (PPAR) regulatory pathway plays a critical role in the regulation of inflammation in central nervous system diseases. In this study, we investigated whether EE attenuates sevoflurane-induced learning and memory disability via the PPAR signaling pathway. Six-day-old mice were treated with 3% sevoflurane for 2 hours daily from postnatal day 6 (P6) to P8. Then, the mice were treated with EE. The effects of sevoflurane on learning and memory function, PPAR-γ expression in the brain, and the numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells and 5-bromodeoxyuridine-positive cells in the hippocampus were determined. Sevoflurane induced neuronal apoptosis and neurogenesis inhibition, which may impair learning and memory in young mice. Furthermore, sevoflurane downregulated PPAR-γ expression. Both EE and the PPAR-γ agonist, rosiglitazone, attenuated sevoflurane-induced neuronal apoptosis, neurogenesis inhibition, and learning and memory impairment. Our findings suggest that EE ameliorated sevoflurane-induced neurotoxicity and learning and memory impairment through the PPAR-γ signaling pathway. PPAR-γ may be a potential therapeutic target for preventing or treating sevoflurane-induced neurotoxicity. Yupeng Zhao, Kaizheng Chen, and Xia Shen Copyright © 2015 Yupeng Zhao et al. All rights reserved. Clinical, Psychopathological, and Personality Characteristics Associated with ADHD among Individuals Seeking Treatment for Gambling Disorder Wed, 01 Jul 2015 06:34:44 +0000 Objectives. (1) To assess the current presence of ADHD symptoms among patients seeking treatment for gambling disorder; (2) to explore clinical and sociodemographic differences between patients who score high and low on the measure of ADHD symptoms; (3) to analyze whether the presence of ADHD symptoms is associated with more severe psychopathology and with specific personality traits; (4) to analyze the mediating role of ADHD symptoms in the relationship between novelty seeking and gambling severity. Method. A total of 354 consecutive patients were administered an extensive battery assessing gambling behavior, psychopathology, and personality traits. Results. Male and female gamblers did not differ significantly in their mean scores on the ADHD measure. However, younger participants aged 18–35 scored higher. Higher ADHD scores were also associated with greater severity of gambling disorder and more general psychopathology. Regarding personality traits, high persistence and self-directedness were negatively related to ADHD scores, while in women alone a positive correlation was found between ADHD scores and scores on harm avoidance and self-transcendence. Conclusion. The presence of ADHD symptoms in both male and female gambling disorder patients may act as an indicator of the severity of gambling, general psychopathology, and dysfunctional personality traits. N. Aymamí, S. Jiménez-Murcia, R. Granero, J. A. Ramos-Quiroga, F. Fernández-Aranda, L. Claes, A. Sauvaget, M. Grall-Bronnec, M. Gómez-Peña, L. G. Savvidou, A. B. Fagundo, A. del Pino-Gutierrez, L. Moragas, M. Casas, E. Penelo, and J. M. Menchón Copyright © 2015 N. Aymamí et al. All rights reserved. Toward a Meta-Analytic Synthesis of the Resting-State fMRI Literature for Clinical Populations Wed, 10 Jun 2015 08:27:44 +0000 Yu-Feng Zang, Xi-Nian Zuo, Michael Milham, and Mark Hallett Copyright © 2015 Yu-Feng Zang et al. All rights reserved. Decreased Resting-State Interhemispheric Functional Connectivity in Parkinson’s Disease Tue, 09 Jun 2015 13:58:15 +0000 Background. Abnormalities in white matter integrity and specific functional network alterations have been increasingly reported in patients with Parkinson’s disease (PD). However, little is known about the inter-hemispheric interaction in PD. Methods. Fifty-one drug naive patients with PD and 51 age- and gender-matched healthy subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI) scans. We compared the inter-hemispheric resting-state functional connectivity between patients with PD and healthy controls, using the voxel-mirrored homotopic connectivity (VMHC) approach. Then, we correlated the results from VMHC and clinical features in PD patients. Results. Relative to healthy subject, patients exhibited significantly lower VMHC in putamen and cortical regions associated with sensory processing and motor control (involving sensorimotor and supramarginal cortex), which have been verified to play a critical role in PD. In addition, there were inverse relationships between the UPDRS motor scores and VMHC in the sensorimotor, and between the illness duration and VMHC in the supramarginal gyrus in PD patients. Conclusions. Our results suggest that the functional coordination between homotopic brain regions is impaired in PD patients, extending previous notions about the disconnection of corticostriatal circuit by providing new evidence supporting a disturbance in inter-hemispheric connections in PD. ChunYan Luo, XiaoYan Guo, Wei Song, Bi Zhao, Bei Cao, Jing Yang, QiYong Gong, and Hui-Fang Shang Copyright © 2015 ChunYan Luo et al. All rights reserved. Altered Synchronizations among Neural Networks in Geriatric Depression Tue, 09 Jun 2015 11:04:06 +0000 Although major depression has been considered as a manifestation of discoordinated activity between affective and cognitive neural networks, only a few studies have examined the relationships among neural networks directly. Because of the known disconnection theory, geriatric depression could be a useful model in studying the interactions among different networks. In the present study, using independent component analysis to identify intrinsically connected neural networks, we investigated the alterations in synchronizations among neural networks in geriatric depression to better understand the underlying neural mechanisms. Resting-state fMRI data was collected from thirty-two patients with geriatric depression and thirty-two age-matched never-depressed controls. We compared the resting-state activities between the two groups in the default-mode, central executive, attention, salience, and affective networks as well as correlations among these networks. The depression group showed stronger activity than the controls in an affective network, specifically within the orbitofrontal region. However, unlike the never-depressed controls, geriatric depression group lacked synchronized/antisynchronized activity between the affective network and the other networks. Those depressed patients with lower executive function has greater synchronization between the salience network with the executive and affective networks. Our results demonstrate the effectiveness of the between-network analyses in examining neural models for geriatric depression. Lihong Wang, Ying-Hui Chou, Guy G. Potter, and David C. Steffens Copyright © 2015 Lihong Wang et al. All rights reserved. An fMRI Study of Local Synchronization in Different Subfrequency Bands during the Continuous Feedback of Finger Force Tue, 09 Jun 2015 07:51:40 +0000 Conventional functional magnetic resonance imaging (fMRI) studies on motor feedback employ periodical blocked paradigm which does not allow frequency analysis of brain activity. Here, we carried out an fMRI study by using a continuous paradigm, that is, continuous (8 min) feedback of finger force. Borrowing an analytic method widely used in resting-state fMRI studies, that is, regional homogeneity (ReHo), we compared the local synchronization in some subfrequency bands between real and sham feedback, and the subbands were defined as Slow-6 (0.0–0.01 Hz), Slow-5 (0.01–0.027 Hz), Slow-4 (0.027–0.073 Hz), Slow-3 (0.073–0.198 Hz), and Slow-2 (0.198–0.25 Hz). Our results revealed that the five subfrequency bands of brain activity contributed to the changes of ReHo between real and sham feedback differently, and, more importantly, the changes in basal ganglia were only manifested in Slow-6, implicating the fact that ReHo in ultraslow band may be associated with the functional significance of BG, that is, motor control. These findings provide novel insights into the neural substrate underlying motor feedback, and properties of the ultraslow band of local synchronization deserve more attention in future explorations. Hang Zhang, Zhong-Zhan Gao, and Yu-Feng Zang Copyright © 2015 Hang Zhang et al. All rights reserved. The Altered Triple Networks Interaction in Depression under Resting State Based on Graph Theory Tue, 09 Jun 2015 07:10:04 +0000 The triple network model (Menon, 2011) has been proposed, which helps with finding a common framework for understanding the dysfunction in core neurocognitive network across multiple disorders. The alteration of the triple networks in the major depression disorder (MDD) is not clear. In our study, the altered interaction of the triple networks, which include default model network (DMN), central executive network (CEN), and salience network (SN), was examined in the MDD by graph theory method. The results showed that the connectivity degree of right anterior insula (rAI) significantly increased in MDD compared with healthy control (HC), and the connectivity degree between DMN and CEN significantly decreased in MDD. These results not only supported the proposal of the triple network model, but also prompted us to understand the dysfunction of neural mechanism in MDD. Hongna Zheng, Lele Xu, Fufang Xie, Xiaojuan Guo, Jiacai Zhang, Li Yao, and Xia Wu Copyright © 2015 Hongna Zheng et al. All rights reserved. Neural Correlates of Associative Memory in the Elderly: A Resting-State Functional MRI Study Tue, 09 Jun 2015 07:09:54 +0000 The neural correlates of associative memory in healthy older adults were investigated by examining the correlation of associative memory performance with spontaneous brain oscillations. Eighty healthy older adults underwent a resting-state functional MRI and took a paired-associative learning test (PALT). Correlations between the amplitude of low-frequency fluctuations (ALFF) as well as fractional ALFF (fALFF) in the whole brain and PALT scores were calculated. We found that spontaneous activity as indexed by both ALFF and fALFF in the parahippocampal gyrus (PHG) was significantly positively correlated with associative memory performance, suggesting that the PHG plays a critical role in associative memory in older people. Weicong Ren, Rui Li, Zhiwei Zheng, and Juan Li Copyright © 2015 Weicong Ren et al. All rights reserved. Altered Spontaneous Brain Activity in Schizophrenia: A Meta-Analysis and a Large-Sample Study Tue, 09 Jun 2015 07:06:38 +0000 Altered spontaneous brain activity as measured by ALFF, fALFF, and ReHo has been reported in schizophrenia, but no consensus has been reached on alternations of these indexes in the disorder. We aimed to clarify the regional alterations in ALFF, fALFF, and ReHo in schizophrenia using a meta-analysis and a large-sample validation. A meta-analysis of activation likelihood estimation was conducted based on the abnormal foci of ten studies. A large sample of 86 schizophrenia patients and 89 healthy controls was compared to verify the results of the meta-analysis. Meta-analysis demonstrated that the alternations in ALFF and ReHo had similar distribution in schizophrenia patients. The foci with decreased ALFF/fALFF and ReHo in schizophrenia were mainly located in the somatosensory cortex, posterior parietal cortex, and occipital cortex; however, foci with increased ALFF/fALFF and ReHo were mainly located in the bilateral striatum, medial temporal cortex, and medial prefrontal cortex. The large-sample study showed consistent findings with the meta-analysis. These findings may expound the pathophysiological hypothesis and guide future research. Yongjie Xu, Chuanjun Zhuo, Wen Qin, Jiajia Zhu, and Chunshui Yu Copyright © 2015 Yongjie Xu et al. All rights reserved. Assessment of Functional Characteristics of Amnestic Mild Cognitive Impairment and Alzheimer’s Disease Using Various Methods of Resting-State FMRI Analysis Tue, 09 Jun 2015 06:37:04 +0000 Resting-state functional magnetic resonance imaging (RS FMRI) has been widely used to analyze functional alterations in amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) patients. Although many clinical studies of aMCI and AD patients using RS FMRI have been undertaken, conducting a meta-analysis has not been easy because of seed selection bias by the investigators. The purpose of our study was to investigate the functional differences in aMCI and AD patients compared with healthy subjects in a meta-analysis. Thus, a multimethod approach using regional homogeneity, amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), and global brain connectivity was used to investigate differences between three groups based on previously published data. According to the choice of RS FMRI approach used, the patterns of functional alteration were slightly different. Nevertheless, patients with aMCI and AD displayed consistently decreased functional characteristics with all approaches. All approaches showed that the functional characteristics in the left parahippocampal gyrus were decreased in AD patients compared with healthy subjects. Although some regions were slightly different according to the different RS FMRI approaches, patients with aMCI and AD showed a consistent pattern of decreased functional characteristics with all approaches. Jungho Cha, Jung-Min Hwang, Hang Joon Jo, Sang Won Seo, Duk L. Na, and Jong-Min Lee Copyright © 2015 Jungho Cha et al. All rights reserved. Diagnostic Prediction for Social Anxiety Disorder via Multivariate Pattern Analysis of the Regional Homogeneity Tue, 09 Jun 2015 06:30:55 +0000 Although decades of efforts have been spent studying the pathogenesis of social anxiety disorder (SAD), there are still no objective biological markers that could be reliably used to identify individuals with SAD. Studies using multivariate pattern analysis have shown the potential value in clinically diagnosing psychiatric disorders with neuroimaging data. We therefore examined the diagnostic potential of regional homogeneity (ReHo) underlying neural correlates of SAD using support vector machine (SVM), which has never been studied. Forty SAD patients and pairwise matched healthy controls were recruited and scanned by resting-state fMRI. The ReHo was calculated as synchronization of fMRI signals of nearest neighboring 27 voxels. A linear SVM was then adopted and allowed the classification of the two groups with diagnostic accuracy of ReHo that was 76.25% (sensitivity = 70%, and specificity = 82.5%, ). Regions showing different discriminating values between diagnostic groups were mainly located in default mode network, dorsal attention network, self-referential network, and sensory networks, while the left medial prefrontal cortex was identified with the highest weight. These results implicate that ReHo has good diagnostic potential in SAD, and thus may provide an initial step towards the possible use of whole brain local connectivity to inform the clinical evaluation. Wenjing Zhang, Xun Yang, Su Lui, Yajing Meng, Li Yao, Yuan Xiao, Wei Deng, Wei Zhang, and Qiyong Gong Copyright © 2015 Wenjing Zhang et al. All rights reserved. Connectome-Scale Assessments of Functional Connectivity in Children with Primary Monosymptomatic Nocturnal Enuresis Tue, 09 Jun 2015 06:28:59 +0000 Primary monosymptomatic nocturnal enuresis (PMNE) is a common developmental disorder in children. Previous literature has suggested that PMNE not only is a micturition disorder but also is characterized by cerebral structure abnormalities and dysfunction. However, the biological mechanisms underlying the disease are not thoroughly understood. Graph theoretical analysis has provided a unique tool to reveal the intrinsic attributes of the connectivity patterns of a complex network from a global perspective. Resting-state fMRI was performed in 20 children with PMNE and 20 healthy controls. Brain networks were constructed by computing Pearson’s correlations for blood oxygenation level-dependent temporal fluctuations among the 2 groups, followed by graph-based network analyses. The functional brain networks in the PMNE patients were characterized by a significantly lower clustering coefficient, global and local efficiency, and higher characteristic path length compared with controls. PMNE patients also showed a reduced nodal efficiency in the bilateral calcarine sulcus, bilateral cuneus, bilateral lingual gyri, and right superior temporal gyrus. Our findings suggest that PMNE includes brain network alterations that may affect global communication and integration. Du Lei, Jun Ma, Jilei Zhang, Mengxing Wang, Kaihua Zhang, Fuqin Chen, Xueling Suo, Qiyong Gong, and Xiaoxia Du Copyright © 2015 Du Lei et al. All rights reserved. Examination of Local Functional Homogeneity in Autism Tue, 09 Jun 2015 06:26:27 +0000 Increasing neuroimaging evidence suggests that autism patients exhibit abnormal brain structure and function. We used the Autism Brain Imaging Data Exchange (ABIDE) sample to analyze locally focal (~8 mm) functional connectivity of 223 autism patients and 285 normal controls from 15 international sites using a recently developed surface-based approach. We observed enhanced local connectivity in the middle frontal cortex, left precuneus, and right superior temporal sulcus, and reduced local connectivity in the right insular cortex. The local connectivity in the right middle frontal gyrus was positively correlated with the total score of the autism diagnostic observation schedule whereas the local connectivity within the right superior temporal sulcus was positively correlated with total subscores of both the communication and the stereotyped behaviors and restricted interests of the schedule. Finally, significant interactions between age and clinical diagnosis were detected in the left precuneus. These findings replicated previous observations that used a volume-based approach and suggested possible neuropathological impairments of local information processing in the frontal, temporal, parietal, and insular cortices. Novel site-variability analysis demonstrated high reproducibility of our findings across the 15 international sites. The age-disease interaction provides a potential target region for future studies to further elucidate the neurodevelopmental mechanisms of autism. Lili Jiang, Xiao-Hui Hou, Ning Yang, Zhi Yang, and Xi-Nian Zuo Copyright © 2015 Lili Jiang et al. All rights reserved. Aberrant Functional Connectivity Architecture in Alzheimer’s Disease and Mild Cognitive Impairment: A Whole-Brain, Data-Driven Analysis Mon, 08 Jun 2015 14:34:47 +0000 The purpose of our study was to investigate whether the whole-brain functional connectivity pattern exhibits disease severity-related alterations in patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Resting-state functional magnetic resonance imaging data were acquired in 27 MCI subjects, 35 AD patients, and 27 age- and gender-matched subjects with normal cognition (NC). Interregional functional connectivity was assessed based on a predefined template which parcellated the brain into 90 regions. Altered whole-brain functional connectivity patterns were identified via connectivity comparisons between the AD and NC subjects. Finally, the relationship between functional connectivity strength and cognitive ability according to the mini-mental state examination (MMSE) was evaluated in the MCI and AD groups. Compared with the NC group, the AD group exhibited decreased functional connectivities throughout the brain. The most significantly affected regions included several important nodes of the default mode network and the temporal lobe. Moreover, changes in functional connectivity strength exhibited significant associations with disease severity-related alterations in the AD and MCI groups. The present study provides novel evidence and will facilitate meta-analysis of whole-brain analyses in AD and MCI, which will be critical to better understand the neural basis of AD. Bo Zhou, Hongxiang Yao, Pan Wang, Zengqiang Zhang, Yafeng Zhan, Jianhua Ma, Kaibin Xu, Luning Wang, Ningyu An, Yong Liu, and Xi Zhang Copyright © 2015 Bo Zhou et al. All rights reserved. Chewing, Stress-Related Diseases, and Brain Function Wed, 20 May 2015 13:35:13 +0000 Kin-ya Kubo, Huayue Chen, Xiaolin Zhou, Jian-Hua Liu, and Olivier Darbin Copyright © 2015 Kin-ya Kubo et al. All rights reserved. Mastication as a Stress-Coping Behavior Mon, 18 May 2015 14:19:58 +0000 Exposure to chronic stress induces various physical and mental effects that may ultimately lead to disease. Stress-related disease has become a global health problem. Mastication (chewing) is an effective behavior for coping with stress, likely due to the alterations chewing causes in the activity of the hypothalamic-pituitary-adrenal axis and autonomic nervous system. Mastication under stressful conditions attenuates stress-induced increases in plasma corticosterone and catecholamines, as well as the expression of stress-related substances, such as neurotrophic factors and nitric oxide. Further, chewing reduces stress-induced changes in central nervous system morphology, especially in the hippocampus and hypothalamus. In rodents, chewing or biting on wooden sticks during exposure to various stressors reduces stress-induced gastric ulcer formation and attenuates spatial cognitive dysfunction, anxiety-like behavior, and bone loss. In humans, some studies demonstrate that chewing gum during exposure to stress decreases plasma and salivary cortisol levels and reduces mental stress, although other studies report no such effect. Here, we discuss the neuronal mechanisms that underline the interactions between masticatory function and stress-coping behaviors in animals and humans. Kin-ya Kubo, Mitsuo Iinuma, and Huayue Chen Copyright © 2015 Kin-ya Kubo et al. All rights reserved. Prefrontal Hemodynamic Changes Associated with Subjective Sense of Occlusal Discomfort Mon, 18 May 2015 07:05:48 +0000 We used functional near-infrared spectroscopy to measure prefrontal brain activity accompanying the physical sensation of oral discomfort that arose when healthy young-adult volunteers performed a grinding motion with mild occlusal elevation (96 μm). We simultaneously evaluated various forms of occlusal discomfort using the visual analogue scale (VAS) and hemodynamic responses to identify the specific prefrontal activity that occurs with increased occlusal discomfort. The Oxy-Hb responses of selected channels in the bilateral frontopolar and dorsolateral prefrontal cortices increased in participants who reported increased severity of occlusal discomfort, while they decreased in those who reported no change or decreased occlusal discomfort during grinding. Moreover, the cumulative values of Oxy-Hb response in some of these channels were statistically significant predictive factors for the VAS scores. A generalized linear model analysis of Oxy-Hb signals in a group of participants who reported increased discomfort further indicated significant cerebral activation in the right frontopolar and dorsolateral prefrontal cortices that overlapped with the results of correlation analyses. Our results suggest that the increased hemodynamic responses in the prefrontal area reflect the top-down control of attention and/or self-regulation against the uncomfortable somatosensory input, which could be a possible marker to detect the subjective sense of occlusal discomfort. Yumie Ono, Goh Kobayashi, Rika Hayama, Ryuhei Ikuta, Minoru Onozouka, Hiroyuki Wake, Atsushi Shimada, Tomoaki Shibuya, and Katsushi Tamaki Copyright © 2015 Yumie Ono et al. All rights reserved. Chew the Pain Away: Oral Habits to Cope with Pain and Stress and to Stimulate Cognition Mon, 18 May 2015 07:03:10 +0000 The acute effects of chewing gum on cognitive performance, stress, and pain have been intensively studied in the last decade. The results have been contradicting, and replication studies proved challenging. Here, we review some of the recent findings of this topic and explore possible explanations for these discrepancies by incorporating knowledge derived from studies into oral habits and bruxism. Both stress and cerebral functional specialization (i.e., the involvement of specific brain structures in distinctive cognitive processes) are hypothesized to play a major role in the underlying physiological mechanisms of the diverse effects of chewing gum on cognition, stress, and pain. Roxane Anthea Francesca Weijenberg and Frank Lobbezoo Copyright © 2015 Roxane Anthea Francesca Weijenberg and Frank Lobbezoo. All rights reserved. Chewing Prevents Stress-Induced Hippocampal LTD Formation and Anxiety-Related Behaviors: A Possible Role of the Dopaminergic System Sun, 17 May 2015 14:13:04 +0000 The present study examined the effects of chewing on stress-induced long-term depression (LTD) and anxiogenic behavior. Experiments were performed in adult male rats under three conditions: restraint stress condition, voluntary chewing condition during stress, and control condition without any treatments except handling. Chewing ameliorated LTD development in the hippocampal CA1 region. It also counteracted the stress-suppressed number of entries to the center region of the open field when they were tested immediately, 30 min, or 60 min after restraint. At the latter two poststress time periods, chewing during restraint significantly increased the number of times of open arm entries in the elevated plus maze, when compared with those without chewing. The in vivo microdialysis further revealed that extracellular dopamine concentration in the ventral hippocampus, which is involved in anxiety-related behavior, was significantly greater in chewing rats than in those without chewing from 30 to 105 min after stress exposure. Development of LTD and anxiolytic effects ameliorated by chewing were counteracted by administering the D1 dopamine receptor antagonist SCH23390, which suggested that chewing may activate the dopaminergic system in the ventral hippocampus to suppress stress-induced anxiogenic behavior. Yumie Ono, So Koizumi, and Minoru Onozuka Copyright © 2015 Yumie Ono et al. All rights reserved. Effects of Mandibular Retrusive Deviation on Prefrontal Cortex Activation: A Functional Near-Infrared Spectroscopy Study Sun, 17 May 2015 13:46:33 +0000 The objective of this study was to evaluate occlusal condition by assessing brain activity in the prefrontal cortex, which is associated with emotion. Functional near-infrared spectroscopy (fNIRS) was used to detect changes in cerebral blood flow in the prefrontal cortex of 12 healthy volunteers. The malocclusion model was a custom-made splint that forced the mandible into retrusion. A splint with no modification was used as a control. The cortical activation during clenching was compared between the retrusive position condition and the control condition. A visual analog scale score for discomfort was also obtained during clenching and used to evaluate the interaction between fNIRS data and psychiatric changes. Activation of the prefrontal cortex was significantly greater during clenching in the mandibular retrusive condition than during clenching in the control condition. Furthermore, Spearman rank-correlation coefficient revealed a parallel relation between prefrontal cortex activation and visual analog scale score for discomfort. These results indicate that fNIRS can be used to objectively evaluate the occlusal condition by evaluating activity in the prefrontal cortex. Takero Otsuka, Ryuichi Yamasaki, Tateshi Shimazaki, Fumihiko Yoshino, Kenichi Sasaguri, and Toshitsugu Kawata Copyright © 2015 Takero Otsuka et al. All rights reserved. Functions of Kinesin Superfamily Proteins in Neuroreceptor Trafficking Sun, 17 May 2015 12:49:21 +0000 Synaptic plasticity is widely regarded as the cellular basis of learning and memory. Understanding the molecular mechanism of synaptic plasticity has been one of center pieces of neuroscience research for more than three decades. It has been well known that the trafficking of α-amino-3-hydroxy-5-methylisoxazoloe-4-propionic acid- (AMPA-) type, N-methyl-D-aspartate- (NMDA-) type glutamate receptors to and from synapses is a key molecular event underlying many forms of synaptic plasticity. Kainate receptors are another type of glutamate receptors playing important roles in synaptic transmission. In addition, GABA receptors also play important roles in modulating the synaptic plasticity. Kinesin superfamily proteins (also known as KIFs) transport various cargos in both anterograde and retrograde directions through the interaction with different adaptor proteins. Recent studies indicate that KIFs regulate the trafficking of NMDA receptors, AMPA receptors, kainate receptors, and GABA receptors and thus play important roles in neuronal activity. Here we review the essential functions of KIFs in the trafficking of neuroreceptor and synaptic plasticity. Na Wang and Junyu Xu Copyright © 2015 Na Wang and Junyu Xu. All rights reserved. Chewing Gum: Cognitive Performance, Mood, Well-Being, and Associated Physiology Sun, 17 May 2015 12:24:45 +0000 Recent evidence has indicated that chewing gum can enhance attention, as well as promoting well-being and work performance. Four studies (two experiments and two intervention studies) examined the robustness of and mechanisms for these effects. Study 1 investigated the acute effect of gum on mood in the absence of task performance. Study 2 examined the effect of rate and force of chewing on mood and attention performance. Study 3 assessed the effects of chewing gum during one working day on well-being and performance, as well as postwork mood and cognitive performance. In Study 4, performance and well-being were reported throughout the workday and at the end of the day, and heart rate and cortisol were measured. Under experimental conditions, gum was associated with higher alertness regardless of whether performance tasks were completed and altered sustained attention. Rate of chewing and subjective force of chewing did not alter mood but had some limited effects on attention. Chewing gum during the workday was associated with higher productivity and fewer cognitive problems, raised cortisol levels in the morning, and did not affect heart rate. The results emphasise that chewing gum can attenuate reductions in alertness, suggesting that chewing gum enhances worker performance. Andrew P. Allen and Andrew P. Smith Copyright © 2015 Andrew P. Allen and Andrew P. Smith. All rights reserved. Chewing and Attention: A Positive Effect on Sustained Attention Sun, 17 May 2015 12:17:14 +0000 Chewing is crushing food not only to aid swallowing and digestion, but also to help stress relief and regulate cognitive function, especially in attention. It is well known that chewing gum is used for sleepiness prevention during work, learning, and driving, suggesting a link between chewing and sustained attention. We hypothesized that chewing elevates attention and/or alertness, leading to improvements in cognitive performance. We carried out a systematic review of the PubMed database. We inspected the attributes of effects on attention in studies investigating the effects of chewing on attention or alertness conducted with pre-post design in healthy subjects, except elderly. We identified 151 references, 22 of which were included: 14 (64%) showed positive attributes of effects on attention, 1 (5%) showed negative attributes of effects on attention, 5 (23%) showed both positive and negative attributes of effects on attention, and 2 (9%) showed no significant attributes of effects on attention. Thus, positive attributes of effects of chewing on attention, especially on sustained attention, were shown in over half of the reports. These effects also appeared with improvement in mood and stress relief and were influenced by time-on-task effect. Further studies are needed, but chewing could be useful for modifying cognitive function. Yoshiyuki Hirano and Minoru Onozuka Copyright © 2015 Yoshiyuki Hirano and Minoru Onozuka. All rights reserved. Bridging the Gap between Statistical and Biological Epistasis in Alzheimer’s Disease Sun, 17 May 2015 09:23:29 +0000 Alzheimer’s disease affects millions of people worldwide and incidence is expected to rise as the population ages, but no effective therapies exist despite decades of research and more than 20 known disease markers. Research has shown that Alzheimer’s disease’s missing heritability remains extensive with an estimated 25% of phenotypic variance unexplained by known variants. The missing heritability may be explained by missing variants or by epistasis. Researchers often focus on individual loci rather than epistatic interactions, which is likely an oversimplification of the underlying biology since most phenotypes are affected by multiple genes. Focusing research efforts on epistasis will be critical to resolving Alzheimer’s disease etiology, and a major key to identifying and properly interpreting key epistatic interactions will be bridging the gap between statistical and biological epistasis. This review covers the current state of epistasis research in Alzheimer’s disease and how researchers can bridge the gap between statistical and biological epistasis to help resolve Alzheimer’s disease etiology. Mark T. W. Ebbert, Perry G. Ridge, and John S. K. Kauwe Copyright © 2015 Mark T. W. Ebbert et al. All rights reserved. Phytochemicals That Regulate Neurodegenerative Disease by Targeting Neurotrophins: A Comprehensive Review Thu, 14 May 2015 11:18:56 +0000 Alzheimer’s disease (AD), characterized by progressive dementia and deterioration of cognitive function, is an unsolved social and medical problem. Age, nutrition, and toxins are the most common causes of AD. However, currently no credible treatment is available for AD. Traditional herbs and phytochemicals may delay its onset and slow its progression and also allow recovery by targeting multiple pathological causes by antioxidative, anti-inflammatory, and antiamyloidogenic properties. They also regulate mitochondrial stress, apoptotic factors, free radical scavenging system, and neurotrophic factors. Neurotrophins such as BDNF, NGF, NT3, and NT4/5 play a vital role in neuronal and nonneuronal responses to AD. Neurotrophins depletion accelerates the progression of AD and therefore, replacing such neurotrophins may be a potential treatment for neurodegenerative disease. Here, we review the phytochemicals that mediate the signaling pathways involved in neuroprotection specifically neurotrophin-mediated activation of Trk receptors and members of superfamily. We focus on representative phenolic derivatives, iridoid glycosides, terpenoids, alkaloids, and steroidal saponins as regulators of neurotrophin-mediated neuroprotection. Although these phytochemicals have attracted attention owing to their in vitro neurotrophin potentiating activity, their in vivo and clinical efficacy trials has yet to be established. Therefore, further research is necessary to prove the neuroprotective effects in preclinical models and in humans. Ramu Venkatesan, Eunhee Ji, and Sun Yeou Kim Copyright © 2015 Ramu Venkatesan et al. All rights reserved. Neuroprotective Effect of Sodium Butyrate against Cerebral Ischemia/Reperfusion Injury in Mice Thu, 07 May 2015 09:52:28 +0000 Sodium butyrate (NaB) is a dietary microbial fermentation product of fiber and serves as an important neuromodulator in the central nervous system. In this study, we further investigated that NaB attenuated cerebral ischemia/reperfusion (I/R) injury in vivo and its possible mechanisms. NaB (5, 10 mg/kg) was administered intragastrically 3 h after the onset of reperfusion in bilateral common carotid artery occlusion (BCCAO) mice. After 24 h of reperfusion, neurological deficits scores were estimated. Morphological examination was performed by electron microscopy and hematoxylin-eosin (H&E) staining. The levels of oxidative stress and inflammatory cytokines were assessed. Apoptotic neurons were measured by TUNEL; apoptosis-related protein caspase-3, Bcl-2, Bax, the phosphorylation Akt (p-Akt), and BDNF were assayed by western blot and immunohistochemistry. The results showed that 10 mg/kg NaB treatment significantly ameliorated neurological deficit and histopathology changes in cerebral I/R injury. Moreover, 10 mg/kg NaB treatment markedly restored the levels of MDA, SOD, IL-1β, TNF-α, and IL-8. 10 mg/kg NaB treatment also remarkably inhibited the apoptosis, decreasing the levels of caspase-3 and Bax and increasing the levels of Bcl-2, p-Akt, and BDNF. This study suggested that NaB exerts neuroprotective effects on cerebral I/R injury by antioxidant, anti-inflammatory, and antiapoptotic properties and BDNF-PI3K/Akt pathway is involved in antiapoptotic effect. Jing Sun, Fangyan Wang, Haixiao Li, Huiqing Zhang, Jiangtao Jin, Wenqian Chen, Mengqi Pang, Junjie Yu, Yiwen He, Jiaming Liu, and Chunfeng Liu Copyright © 2015 Jing Sun et al. All rights reserved. Assessing Apoptosis Gene Expression Profiling with a PCR Array in the Hippocampus of Ts65Dn Mice Tue, 05 May 2015 13:57:08 +0000 It is well known that Down syndrome (DS) is a condition in which extra genetic material causes delays in the way a child develops, both mentally and physically. Intellectual disability is the foremost and most debilitating trait, which caused loss of cognitive abilities and the development of early onset Alzheimer’s disease (AD). Ts65Dn mice were used in this study. We isolated the hippocampus. First, we used transmission scanning electron microscopy to directly observe the hippocampus and confirm if apoptosis had occurred. Second, we customized a PCR array with 53 genes, including several important genes related to cell apoptosis. Gene expression was detected by RT-PCR. There were varying degrees of changes characteristic of apoptosis in the hippocampus of Ts65Dn mice, which mainly included the following: nuclear membrane thinning, unevenly distributed chromosomes, the production of chromatin crescents, and pyknosis of the nuclei with some nuclear fragmentation. Meanwhile, three genes (API5, AIFM1, and NFκB1) showed changes of expression in the hippocampus of Ts65Dn mice compared with normal mice. Only NFκB1 expression was significantly increased, while the expressions of API5 and AIFM1 were notably decreased. The fold changes in the expression of API5, AIFM1, and NFκB1 were 11.55, 5.94, and 3.11, respectively. However, some well-known genes related to cell apoptosis, such as the caspase family, Bcl-2, Bad, Bid, Fas, and TNF, did not show changes in expression levels. The genes we found which were differentially expressed in the hippocampus of Ts65Dn mice may be closely related to cell apoptosis. PCR array technology can assist in the screening and identification of genes involved in apoptosis. Bin Yu, Bin Zhang, Wen-bo Zhou, Qiu-wei Wang, Pei Yuan, Yu-qi Yang, and Jing Kong Copyright © 2015 Bin Yu et al. All rights reserved. How Do Families of Children with Down Syndrome Perceive Speech Intelligibility in Turkey? Tue, 21 Apr 2015 14:08:53 +0000 Childhood verbal apraxia has not been identified or treated sufficiently in children with Down syndrome but recent research has documented that symptoms of childhood verbal apraxia can be found in children with Down syndrome. But, it is not routinely diagnosed in this population. There is neither an assessment tool in Turkish nor any research on childhood verbal apraxia although there is a demand not only for children with Down syndrome but also for normally developing children. The study examined if it was possible to determine oral-motor difficulties and childhood verbal apraxia features in children with Down syndrome through a survey. The survey was a parental report measure. There were 329 surveys received. Results indicated that only 5.6% of children with Down syndrome were diagnosed with apraxia, even though many of the subject children displayed clinical features of childhood verbal apraxia. The most frequently reported symptoms of childhood verbal apraxia in literature were displayed by the children with Down syndrome in the study. Parents could identify childhood verbal apraxia symptoms using parent survey. This finding suggests that the survey can be developed that could serve as a screening tool for a possible childhood verbal apraxia diagnosis in Turkey. Bülent Toğram Copyright © 2015 Bülent Toğram. All rights reserved. Astroglia-Microglia Cross Talk during Neurodegeneration in the Rat Hippocampus Tue, 21 Apr 2015 14:04:26 +0000 Brain injury triggers a progressive inflammatory response supported by a dynamic astroglia-microglia interplay. We investigated the progressive chronic features of the astroglia-microglia cross talk in the perspective of neuronal effects in a rat model of hippocampal excitotoxic injury. N-Methyl-D-aspartate (NMDA) injection triggered a process characterized within 38 days by atrophy, neuronal loss, and fast astroglia-mediated S100B increase. Microglia reaction varied with the lesion progression. It presented a peak of tumor necrosis factor-α (TNF-α) secretion at one day after the lesion, and a transient YM1 secretion within the first three days. Microglial glucocorticoid receptor expression increased up to day 5, before returning progressively to sham values. To further investigate the astroglia role in the microglia reaction, we performed concomitant transient astroglia ablation with L-α-aminoadipate and NMDA-induced lesion. We observed a striking maintenance of neuronal death associated with enhanced microglial reaction and proliferation, increased YM1 concentration, and decreased TNF-α secretion and glucocorticoid receptor expression. S100B reactivity only increased after astroglia recovery. Our results argue for an initial neuroprotective microglial reaction, with a direct astroglial control of the microglial cytotoxic response. We propose the recovery of the astroglia-microglia cross talk as a tissue priority conducted to ensure a proper cellular coordination that retails brain damage. Montserrat Batlle, Lorenzo Ferri, Carmen Andrade, Francisco-Javier Ortega, Jose M. Vidal-Taboada, Marco Pugliese, Nicole Mahy, and Manuel J. Rodríguez Copyright © 2015 Montserrat Batlle et al. All rights reserved. The Kampo Medicine Yokukansan Decreases MicroRNA-18 Expression and Recovers Glucocorticoid Receptors Protein Expression in the Hypothalamus of Stressed Mice Sun, 19 Apr 2015 12:13:59 +0000 It is well known that glucocorticoid receptor (GR) signaling regulates the hypothalamic-pituitary-adrenal (HPA) axis, and GR expression level is associated with HPA axis activity. Recent studies revealed that microRNA- (miR-) 18 and/or 124a are candidate negative regulators of GR in the brain. The Kampo medicine Yokukansan (YKS) can affect psychological symptoms such as depression and anxiety that are associated with stress responses. In this study, we evaluated the effect of YKS on miR-18 and 124a and GR levels in mice exposed to stress. We found that YKS pretreatment normalized elevated plasma corticosterone levels in stress-exposed mice. In addition, GR mRNA levels were downregulated in the brain following stress exposure. While miR-124a expression levels were not altered in the hypothalamus of stress-exposed mice, miR-18 levels decreased in the hypothalamus of YKS-pretreated mice after stress exposure. Finally, GR protein levels in the paraventricular nucleus (PVN) of the hypothalamus after stress exposure recovered in YKS-pretreated mice. Collectively, these data suggest that YKS normalizes GR protein levels by regulating miR-18 expression in the hypothalamus, thus normalizing HPA axis activity following stress exposure. Shoko Shimizu, Takashi Tanaka, Takashi Takeda, Masaya Tohyama, and Shingo Miyata Copyright © 2015 Shoko Shimizu et al. All rights reserved. Familial Parkinson’s Disease/Parkinsonism Sun, 19 Apr 2015 12:08:55 +0000 Hiroyuki Tomiyama, Suzanne Lesage, Eng-King Tan, and Beom S. Jeon Copyright © 2015 Hiroyuki Tomiyama et al. All rights reserved. SNCA Gene, but Not MAPT, Influences Onset Age of Parkinson’s Disease in Chinese and Australians Wed, 15 Apr 2015 08:18:39 +0000 Background. α-Synuclein (SNCA) and microtubule-associated protein tau (MAPT) are the two major genes independently, but not jointly, associated with susceptibility for Parkinson’s disease (PD). The SNCA gene has recently been identified as a major modifier of age of PD onset. Whether MAPT gene synergistically influences age of onset of PD is unknown. Objective. To investigate independent and joint effects of MAPT and SNCA on PD onset age. Methods. 412 patients with PD were recruited from the Australian PD Research Network (123) and the Neurology Department, Ruijin Hospital Affiliated to Shanghai Jiaotong University, China (289). MAPT (rs17650901) tagging H1/H2 haplotype and SNCA (Rep1) were genotyped in the Australian cohort, and MAPT (rs242557, rs3744456) and SNCA (rs11931074, rs894278) were genotyped in the Chinese cohort. SPSS regression analysis was used to test genetic effects on age at onset of PD in each cohort. Results. SNCA polymorphisms associated with the onset age of PD in both populations. MAPT polymorphisms did not enhance such association in either entire cohort. Conclusion. This study suggests that, in both ethnic groups, SNCA gene variants influence the age at onset of PD and α-synuclein plays a key role in the disease course of PD. Yue Huang, Gang Wang, Dominic Rowe, Ying Wang, John B. J. Kwok, Qin Xiao, Frank Mastaglia, Jun Liu, Sheng-Di Chen, and Glenda Halliday Copyright © 2015 Yue Huang et al. All rights reserved. Molecular Mechanoneurobiology: An Emerging Angle to Explore Neural Synaptic Functions Tue, 14 Apr 2015 11:53:13 +0000 Neural synapses are intercellular asymmetrical junctions that transmit biochemical and biophysical information between a neuron and a target cell. They are very tight, dynamic, and well organized by many synaptic adhesion molecules, signaling receptors, ion channels, and their associated cytoskeleton that bear forces. Mechanical forces have been an emerging factor in regulating axon guidance and growth, synapse formation and plasticity in physiological and pathological brain activity. Therefore, mechanical forces are undoubtedly exerted on those synaptic molecules and modulate their functions. Here we review current progress on how mechanical forces regulate receptor-ligand interactions, protein conformations, ion channels activation, and cytoskeleton dynamics and discuss how these regulations potentially affect synapse formation, stabilization, and plasticity. Wei Hu, Chenyi An, and Wei J. Chen Copyright © 2015 Wei Hu et al. 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. 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. 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. 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. 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