Cytokine pathway disruption in a mouse model of schizophrenia induced by Munc18-1a overexpression in the brain

Background: An accumulating body of evidence points to the significance of neuroinflammation and immunogenetics in schizophrenia, and an imbalance of cytokines in the central nervous system (CNS) has been suggested to be associated with the disorder. Munc18-overexpressing mice (Munc18-OE) have provided a model for the study of the alterations that may underlie the symptoms of subjects with schizophrenia. The aim of the present study was to elucidate the involvement of neuroinflammation and cytokine imbalance in this model. Methods: Cytokines were evaluated in the cortex and the striatum of Munc18-OE and wild-type (WT) mice by enzyme-linked immunosorbent assay (ELISA). Protein levels of specific microglia and macrophage, astrocytic and neuroinflammation markers were quantified by western blot in the cortex and the striatum of Munc18-OE and WT mice. Results: Each cytokine evaluated (Interferon-gamma (IFN-gamma), Tumor Necrosis Factor-alpha (TNF-alpha), Interleukin-2 (IL-2) and CCL2 chemokine) was present at higher levels in the striatum of Munc18-OE mice than WT. Cortical TNF-alpha and IL-2 levels were significantly lower in Munc18-OE mice than WT mice. The microglia and macrophage marker CD11b was lower in the cortexes of Munc18-OE mice than WT, but no differences were observed in the striatum. Glial Fibrillary Acidic Protein (GFAP) and Nuclear Factor-kappaB (NF-kappa B)p65 levels were not different between the groups. Interleukin-1beta (IL-1 beta) and IL-6 levels were beneath detection limits. Conclusions: The disrupted levels of cytokines detected in the brain of Munc18-OE mice was found to be similar to clinical reports and endorses study of this type for analysis of this aspect of the disorder. The lower CD11b expression in the cortex but not in the striatum of the Munc18-OE mice may reflect differences in physiological activity. The cytokine expression pattern observed in Munc18-OE mice is similar to a previously published model of schizophrenia caused by maternal immune activation. Together, these data suggest a possible role for an immune imbalance in this disorder.

GFAP Isoforms in Adult Mouse Brain with a Focus on Neurogenic Astrocytes and Reactive Astrogliosis in Mouse Models of Alzheimer Disease

24 p.

Plasma brain-derived neurotrophic factor levels, learning capacity and cognition in patients with first episode psychosis

Background: Cognitive impairments are seen in first psychotic episode (FEP) patients. The neurobiological underpinnings that might underlie these changes remain unknown. The aim of this study is to investigate whether Brain Derived Neurotrophic Factor (BDNF) levels are associated with cognitive impairment in FEP patients compared with healthy controls. Methods: 45 FEP patients and 45 healthy controls matched by age, gender and educational level were selected from the Basque Country area of Spain. Plasma BDNF levels were assessed in healthy controls and in patients. A battery of cognitive tests was applied to both groups, with the patients being assessed at 6 months after the acute episode and only in those with a clinical response to treatment. Results: Plasma BDNF levels were altered in patients compared with the control group. In FEP patients, we observed a positive association between BDNF levels at six months and five cognitive domains (learning ability,immediate and delayed memory, abstract thinking and processing speed) which persisted after controlling for medications prescribed, drug use, intelligence quotient (IQ) and negative symptoms. In the healthy control group, BDNF levels were not associated with cognitive test scores. Conclusion: Our results suggest that BDNF is associated with the cognitive impairment seen after a FEP. Further investigations of the role of this neurotrophin in the symptoms associated with psychosis onset are warranted.

A detailed investigation of classification methods for vowel speech imagery recognition

Accurate and fast decoding of speech imagery from electroencephalographic (EEG) data could serve as a basis for a new generation of brain computer interfaces (BCIs), more portable and easier to use. However, decoding of speech imagery from EEG is a hard problem due to many factors. In this paper we focus on the analysis of the classification step of speech imagery decoding for a three-class vowel speech imagery recognition problem. We empirically show that different classification subtasks may require different classifiers for accurately decoding and obtain a classification accuracy that improves the best results previously published. We further investigate the relationship between the classifiers and different sets of features selected by the common spatial patterns method. Our results indicate that further improvement on BCIs based on speech imagery could be achieved by carefully selecting an appropriate combination of classifiers for the subtasks involved.

Behavioral, neurochemical and morphological changes induced by the overexpression of munc18-1a in brain of mice: relevance to schizophrenia

Overexpression of the mammalian homolog of the unc-18 gene (munc18-1) has been described in the brain of subjects with schizophrenia. Munc18-1 protein is involved in membrane fusion processes, exocytosis and neurotransmitter release. A transgenic mouse strain that overexpresses the protein isoform munc18-1a in the brain was characterized. This animal displays several schizophrenia-related behaviors, supersensitivity to hallucinogenic drugs and deficits in prepulse inhibition that reverse after antipsychotic treatment. Relevant brain areas (that is, cortex and striatum) exhibit reduced expression of dopamine D-1 receptors and dopamine transporters together with enhanced amphetamine-induced in vivo dopamine release. Magnetic resonance imaging demonstrates decreased gray matter volume in the transgenic animal. In conclusion, the mouse overexpressing brain munc18-1a represents a new valid animal model that resembles functional and structural abnormalities in patients with schizophrenia.

An Algebraic Preservation Theorem for Aleph-Zero Categorical Quantified Constraint Satisfaction

23 p. -- An extended abstract of this work appears in the proceedings of the 2012 ACM/IEEE Symposium on Logic in Computer Science

Black Holes, Cosmological Solutions, Future Singularities, and Their Thermodynamical Properties in Modified Gravity Theorie

54 p.

The interactive brain hypothesis

Enactive approaches foreground the role of interpersonal interaction in explanations of social understanding. This motivates, in combination with a recent interest in neuroscientific studies involving actual interactions, the question of how interactive processes relate to neural mechanisms involved in social understanding. We introduce the Interactive Brain Hypothesis (IBH) in order to help map the spectrum of possible relations between social interaction and neural processes. The hypothesis states that interactive experience and skills play enabling roles in both the development and current function of social brain mechanisms, even in cases where social understanding happens in the absence of immediate interaction. We examine the plausibility of this hypothesis against developmental and neurobiological evidence and contrast it with the widespread assumption that mindreading is crucial to all social cognition. We describe the elements of social interaction that bear most directly on this hypothesis and discuss the empirical possibilities open to social neuroscience. We propose that the link between coordination dynamics and social understanding can be best grasped by studying transitions between states of coordination. These transitions form part of the self-organization of interaction processes that characterize the dynamics of social engagement. The patterns and synergies of this self-organization help explain how individuals understand each other. Various possibilities for role-taking emerge during interaction, determining a spectrum of participation. This view contrasts sharply with the observational stance that has guided research in social neuroscience until recently. We also introduce the concept of readiness to interact to describe the practices and dispositions that are summoned in situations of social significance (even if not interactive). This latter idea links interactive factors to more classical observational scenarios.

More than one language in the brain

Boeckx C., M.C. Horno & J.L. Mendívil (Eds.)

Stability analysis of RF amplifiers based on MIMO pole-zero identification

Spurious oscillations are one of the principal issues faced by microwave and RF circuit designers. The rigorous detection of instabilities or the characterization of measured spurious oscillations is still an ongoing challenge. This project aims to create a new stability analysis CAD program that tackles this chal- lenge. Multiple Input Multiple Output (MIMO) pole-zero identification analysis is introduced on the program as a way to create new methods to automate the stability analysis process and to help designers comprehend the obtained results and prevent incorrect interpretations. The MIMO nature of the analysis contributes to eliminate possible controllability and observability losses and helps differentiate mathematical and physical quasi-cancellations, products of overmodeling. The created program reads Single Input Single Output (SISO) or MIMO frequency response data, and determines the corresponding continuous transfer functions with Vector Fitting. Once the transfer function is calculated, the corresponding pole/zero diagram is mapped enabling the designers to analyze the stability of an amplifier. Three data processing methods are introduced, two of which consist of pole/zero elimina- tions and the latter one on determining the critical nodes of an amplifier. The first pole/zero elimination method is based on eliminating non resonant poles, whilst the second method eliminates the poles with small residue by assuming that their effect on the dynamics of a system is small or non-existent. The critical node detection is also based on the residues; the node at which the effect of a pole on the dynamics is highest is defined as the critical node. In order to evaluate and check the efficiency of the created program, it is compared via examples with another existing commercial stability analysis tool (STAN tool). In this report, the newly created tool is proved to be as rigorous as STAN for detecting instabilities. Additionally, it is determined that the MIMO analysis is a very profitable addition to stability analysis, since it helps to eliminate possible problems of loss of controllability, observability and overmodeling.

Integrated treatment of first episode psychosis with online training (e-learning): study protocol for a randomised controlled trial

Background: The integrated treatment of first episode psychosis has been shown to improve functionality and negative symptoms in previous studies. In this paper, we describe a study of integrated treatment (individual psychoeducation complementary to pharmacotherapy) versus treatment as usual, comparing results at baseline with those at 6-month re-assessment (at the end of the study) for these patients, and online training of professionals to provide this complementary treatment, with the following objectives: 1) to compare the efficacy of individual psychoeducation as add-on treatment versus treatment as usual in improving psychotic and mood symptoms; 2) to compare adherence to medication, functioning, insight, social response, quality of life, and brain-derived neurotrophic factor, between both groups; and 3) to analyse the efficacy of online training of psychotherapists. Methods/design: This is a single-blind randomised clinical trial including patients with first episode psychosis from hospitals across Spain, randomly assigned to either a control group with pharmacotherapy and regular sessions with their psychiatrist (treatment as usual) or an intervention group with integrated care including treatment as usual plus a psychoeducational intervention (14 sessions). Training for professionals involved at each participating centre was provided by the coordinating centre (University Hospital of Alava) through video conferences. Patients are evaluated with an extensive battery of tests assessing clinical and sociodemographic characteristics (Positive and Negative Syndrome Scale, State-Trait Anxiety Inventory, Liebowitz Social Anxiety Scale, Hamilton Rating Scale for Depression, Scale to Assess Unawareness of Mental Disorders, Strauss and Carpenter Prognostic Scale, Global Assessment of Functioning Scale, Morisky Green Adherence Scale, Functioning Assessment Short Test, World Health Organization Quality of Life instrument WHOQOL-BREF (an abbreviated version of the WHOQOL-100), and EuroQoL questionnaire), and brain-derived neurotrophic factor levels are measured in peripheral blood at baseline and at 6 months. The statistical analysis, including bivariate analysis, linear and logistic regression models, will be performed using SPSS. Discussion: This is an innovative study that includes the assessment of an integrated intervention for patients with first episode psychosis provided by professionals who are trained online, potentially making it possible to offer the intervention to more patients.

Cerebral hemodynamics during graded Valsalva maneuvers

The Valsalva maneuver (VM) produces large and abrupt changes in mean arterial pressure (MAP) that challenge cerebral blood flow and oxygenation. We examined the effect of VM intensity on middle cerebral artery blood velocity (MCAv) and cortical oxygenation responses during (phases I-III) and following (phase IV) a VM. Healthy participants (n = 20 mean +/- SD: 27 +/- 7 years) completed 30 and 90% of their maximal VM mouth pressure for 10 s (order randomized) whilst standing. Beat-to-beat MCAv, cerebral oxygenation (NIRS) and MAP across the different phases of the VM are reported as the difference from standing baseline. There were significant interaction (phase * intensity) effects for MCAv, total oxygenation index (TOI) and MAP (all P < 0.01). MCAv decreased during phases II and III (P < 0.01), with the greatest decrease during phase III (-5 +/- 8 and -19 +/- 15 cm.s(-1) for 30 and 90% VM, respectively). This pattern was also evident in TOI (phase III: -1 +/- 1 and -5 +/- 4%, both P < 0.05). Phase IV increased MCAv (22 +/- 15 and 34 +/- 23 cm.s(-1)), MAP (15 +/- 14 and 24 +/- 17 mm Hg) and TOI (5 +/- 6 and 7 +/- 5%) relative to baseline (all P < 0.05). Cerebral autoregulation, indexed, as the % MCAv/%MAP ratio, showed a phase effect only (P < 0.001), with the least regulation during phase IV (2.4 +/- 3.0 and 3.2 +/- 2.9). These data illustrate that an intense VM profoundly affects cerebral hemodynamics, with a reactive hyperemia occurring during phase IV following modest ischemia during phases II and III.

Never-resting microglia: physiological roles in the healthy brain and pathological implications

Microglia are largely known as the major orchestrators of the brain inflammatory response. As such, they have been traditionally studied in various contexts of disease, where their activation has been assumed to induce a wide range of detrimental effects. In the last few years, a series of discoveries have challenged the current view of microglia, showing their active and positive contribution to normal brain function. This Research Topic will review the novel physiological roles of microglia in the developing, mature and aging brain, under non-pathological conditions. In particular, this Research Topic will discuss the cellular and molecular mechanisms by which microglia contribute to the formation, pruning and plasticity of synapses; the maintenance of the blood brain barrier; the regulation of adult neurogenesis and hippocampal learning; and neuronal survival, among other important roles. Because these novel findings defy our understanding of microglial function in health as much as in disease, this Research Topic will also summarize the current view of microglial nomenclature, phenotypes, origin and differentiation, sex differences, and contribution to various brain pathologies. Additionally, novel imaging approaches and molecular tools to study microglia in their non-activated state will be discussed. In conclusion, this Research Topic seeks to emphasize how the current research in neuroscience is challenged by never-resting microglia.

Estudio de señales cerebrales y aplicación a cojín elevador para discapacitados.

[ES]Estudio de obtención de señales cerebrales, creación de sensores de electroencefalograma y circuito que procesa frecuencias cerebrales para control de un prototipo de cojín elevador que ayude a personas discapacitadas a levantarse de un asiento con el fin de dar los primeros pasos en la creación de un exoesqueleto controlado cerebralmente.

Desarrollo de un prototipo de exoesqueleto básico activado con una señal cerebral.

[ES]En este documento se estudia el desarrollo de una aplicación electrónica para la ayuda a gente con movilidad reducida a través de unos sensores cerebrales que permitan el análisis de la iniciativa de la persona a realizar acciones que de otra manera no podría realizar. El concepto completo consiste en el diseño del sensor que el paciente se colocaría en la cabeza, el tratamiento de la información extraída y la actuación por medio de una solución mecánica, como un conjunto cilindro-pistón para el futuro desarrollo de un sistema de ayuda a la movilidad.