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Changes of intestinal permeability (IP) have been extensively investigated in inflammatory bowel diseases (IBD) and celiac disease (CD), underpinned by a known unbalance between microbiota, IP and immune responses in the gut. Recently the influence of IP on brain function has greatly been appreciated. Previous works showed an increased IP that preceded experimental autoimmune encephalomyelitis development and worsened during disease with disruption of TJ. Moreover, studying co-morbidity between Crohn's disease and MS, a report described increased IP in a minority of cases with MS. In a recent work we found that an alteration of IP is a relatively frequent event in relapsing-remitting MS, with a possible genetic influence on the determinants of IP changes (as inferable from data on twins); IP changes included a deficit of the active mechanism of absorption from intestinal lumen. The results led us to hypothesize that gut may contribute to the development of MS, as suggested by another previous work of our group: a population of CD8+CD161high T cells, belonging to the mucosal-associated invariant T (MAIT) cells, a gut- and liver-homing subset, proved to be of relevance for MS pathogenesis. We eventually suggest future lines of research on IP in MS: studies on IP changes in patients under first-line oral drugs may result useful to improve their therapeutic index; correlating IP and microbiota changes, or IP and blood-brain barrier changes may help clarify disease pathogenesis; exploiting the IP data to disclose co-morbidities in MS, especially with CD and IBD, may be important for patient care. [ABSTRACT FROM AUTHOR]

People at ultra-high risk (UHR) of psychosis have ∼30% chance of developing the illness within two years. A range of pharmacological and psychosocial interventions are now available but there is great individual variation in clinical response. Here we examine the evidence for clinically applicable predictors of clinical response in people at UHR of psychosis. We report that currently there are no reliable predictive markers that can be used to optimise treatment. We argue that there is an urgent need for a better understanding of why some people at UHR of psychosis benefit from a certain treatment whereas others do not. This information will help clinicians make more-effective treatment decisions, and improve long-term clinical outcomes in this population. [ABSTRACT FROM AUTHOR]

Several immunomodulatory treatments are currently available for relapsing-remitting forms of multiple sclerosis (RRMS). Interferon beta (IFN) was the first therapeutic intervention able to modify the course of the disease and it is still the most used first-line treatment in RRMS. Though two decades have passed since IFN-β was introduced in the management of MS, it remains a valid approach because of its good benefit/risk profile. This is witnessed by new efforts of pharmaceutical industry to improve this line: a PEGylated form of subcutaneous IFN-β 1a, (Plegridy ® ) with a longer half-life, has been recently approved in RRMS. This review will survey the various stages of the use of type I IFN in MS, with special attention to the effect of the treatment on the supposed viral etiologic factors associated to the disease. The antiviral activities of IFN (that initially prompted its use as immunomodulatory agent in MS), and the mounting evidences in favor of a viral etiology in MS, allowed us to outline a re-appraisal from etiology to therapy and back. [ABSTRACT FROM AUTHOR]

Despite five decades of search for clinically meaningful 'biomarkers' in schizophrenia there are still no common tests to inform diagnosis or treatment. Our aim was to understand why it has been so difficult to convert biological findings into clinical tests. We categorized all PubMed-indexed articles investigating psychosis-related biomarkers to date (over 3200). Studies showed an evident publication bias, a confusing array of terminology, and few systematic efforts at longitudinal evaluation or external validation. Fewer than 200 studies investigated biomarkers, longitudinally, for prediction of illness course and treatment response. These biomarkers were then evaluated in terms of their statistical reliability and clinical effect size. Only one passed our a priori threshold for clinical applicability. This is a modest record. In order to promote real progress, the field needs: (a) consistent use of terminology so that studies can be compared; (b) a system of standardized universal reporting to overcome the existing publication bias; and (c) practical criteria [a prototype is suggested here] for assessing the clinical applicability of the findings. [ABSTRACT FROM AUTHOR]

Abstract: Individuals born very preterm (VPT) are at risk of neurodevelopmental damage and of adverse educational outcomes in childhood and adolescence. The present study used voxel-based morphometry to investigate the association between grey matter and white matter volume and measures of language and executive functioning in VPT born adolescents and term-born controls by gender. VPT individuals (N =218) and controls (N =127) underwent neuropsychological assessment and MRI at age 14–15 as part of a longitudinal study. Differential associations were found between spelling scores and frontal regional grey matter volume when group (VPT and control) and gender (males and females) were investigated. A main effect of group demonstrated a weaker association in VPT adolescents relative to controls between grey matter volume in the left medial and right superior frontal gyri and spelling scores. A main effect of gender revealed spelling scores to be correlated with grey matter volume in the right superior frontal gyrus in females to a greater extent than in males. Furthermore, a significant interaction between group and gender was detected in two regions. Spelling scores showed a stronger association with grey matter volume in a cluster with local maxima in the left medial frontal cortex extending to the caudate nucleus in VPT females than in control females and a weaker association in VPT males compared to control males. In addition, spelling scores showed a stronger association with grey matter volume in left middle frontal gyrus in VPT males compared to control males and a weaker association in VPT females than in control females. When group and gender were investigated, there were no statistically different correlations between structural brain volumes and performance on reading and executive function tests. These data demonstrate that the typical structure–function relationship in respect to spelling abilities appears to be altered in individuals born preterm and the processes underpinning this divergence may be subject to gender-specific influences. [Copyright &y& Elsevier]

Abstract: Both schizophrenia and bipolar disorder have been associated with progressive changes in grey matter (GM) volume. However, the temporal trajectories of these changes are poorly understood. The aim of this study was to assess longitudinal changes in grey matter volume subsequent to the first episode of schizophrenia and of affective psychoses. Adolescent patients with a first episode psychosis (n =26) were scanned twice using magnetic resonance imaging, at first presentation and after a 3-year follow-up period. An age-matched group of healthy volunteers (n =17) was scanned at the same time points. Within-group and between-group changes in regional grey matter volume were examined using voxel-based morphometry. There were significant group by time interactions (p FDRcorr <0.05) in the frontal, temporal, parietal, cerebellar cortex, and in the thalamus, mainly reflecting longitudinal reductions in the controls but not in the patients. Subdivision of the patient group revealed that there were similar longitudinal reductions in patients with affective psychoses as in the controls but no volumetric changes in patients with schizophrenia. Psychosis with onset in adolescence or early adulthood may be associated with a delay or a loss of longitudinal reductions in regional grey matter volume that normally occur at this stage of development. These changes may be specific to schizophrenia. [Copyright &y& Elsevier]

Summary: Over a century after Freud’s attempt to establish psychoanalysis as a natural science, there is renewed interest in the integration of psychoanalytic and neuroscientific findings within a single theoretical and experimental framework. However, it is important that any intellectual exchange is not motivated only by declining confidence in psychoanalytic theory and practice or awareness of the rising fortunes of the brain sciences. The present paper considers three possible ways in which psychoanalysis and neuroscience might be integrated. These include the investigation of the neurological organisation of psychoanalytically defined phenomena; the evaluation of psychoanalytic theories based on their neurobiological evidence; and the use of neuroimaging techniques to assess the progress and outcome of psychoanalytic treatment. The author argues that these exercises are unlikely to provide psychoanalysis with the “unlimited opportunities for overcoming its uncertainties and doubts” that some have anticipated. For instance, the argument that mapping psychoanalytically defined phenomena in the brain may provide biological validity to these phenomena should be considered an expression of logical confusion; the evaluation of psychoanalytic theories based on their biological evidence is critically dependent on speculative interpretation of what the theories predict at neuronal level; and the supposedly objective evaluation of the progress and outcome of psychoanalytic treatment on the basis of neurobiological data relies on the subjective reports of the patient and analyst. In light of this conclusion, there are a number of outstanding questions which remain to be addressed, including whether psychoanalysis should adhere to scientific canons and whether this would necessarily require an experimental methodology. [ABSTRACT FROM AUTHOR]

Abstract: Emotional liability and mood dysregulation characterize bipolar disorder (BD), yet no study has examined effective connectivity between parahippocampal gyrus and prefrontal cortical regions in ventromedial and dorsal/lateral neural systems subserving mood regulation in BD. Participants comprised 46 individuals (age range: 18–56 years): 21 with a DSM-IV diagnosis of BD, type I currently remitted; and 25 age- and gender-matched healthy controls (HC). Participants performed an event-related functional magnetic resonance imaging paradigm, viewing mild and intense happy and neutral faces. We employed dynamic causal modeling (DCM) to identify significant alterations in effective connectivity between BD and HC. Bayes model selection was used to determine the best model. The right parahippocampal gyrus (PHG) and right subgenual cingulate gyrus (sgCG) were included as representative regions of the ventromedial neural system. The right dorsolateral prefrontal cortex (DLPFC) region was included as representative of the dorsal/lateral neural system. Right PHG–sgCG effective connectivity was significantly greater in BD than HC, reflecting more rapid, forward PHG–sgCG signaling in BD than HC. There was no between-group difference in sgCG–DLPFC effective connectivity. In BD, abnormally increased right PHG–sgCG effective connectivity and reduced right PHG activity to emotional stimuli suggest a dysfunctional ventromedial neural system implicated in early stimulus appraisal, encoding and automatic regulation of emotion that may represent a pathophysiological functional neural mechanism for mood dysregulation in BD. [Copyright &y& Elsevier]

Background: The majority of affective psychopathology is rooted early in life and first emerges during childhood and adolescence. However, little is known about how genetic vulnerability affects brain structure and function in childhood since the vast majority of studies published so far have been conducted on adult participants. The present investigation examined for the first time the effects of catechol-O-methyltransferase (COMT) valine (val) 158 methionine (met) (val158met) polymorphism, which has been shown to moderate predisposition to negative mood and affective disorders, on brain structure and function in children. Methods: Voxel-based morphometry and functional magnetic resonance imaging were used to measure gray matter volume and emotional reactivity in 50 children aged between 10 and 12 years. We tested the hypothesis that met158 allele affects structural brain development and confers heightened reactivity within the affective frontolimbic circuit in children. Results: The met158 allele was positively associated with gray matter volume in the left hippocampal head where genotype accounted for 59% of interindividual variance. In addition, the met158 allele was positively associated with neuronal responses to fearful relative to neutral facial expressions in the right parahippocampal gyrus where genotype accounted for 14% of the interindividual variance. Conclusions: These results indicate that the met158 allele is associated with increased gray matter volume and heightened reactivity during emotional processing within the limbic system in children as young as 10 to 12 years of age. These findings are consistent with the notion that genetic factors affect brain function to moderate vulnerability to affective psychopathology from childhood. [Copyright &y& Elsevier]

Background: Catechol-O-methyltransferase (COMT) is essential for dopamine metabolism in the brain, and normal variation in the COMT Val158Met polymorphism can influence regional brain function during cognitive tasks. How this is affected when central dopamine function is perturbed is unclear. We addressed this by comparing the effects of COMT Val158Met genotype on cortical activation during a task of executive functions in healthy and schizophrenic subjects. Methods: We studied 90 subjects comprising 48 healthy volunteers (15 Met158/Met158, 20 Val158/Met158, and 13 Val158/Val158) and 42 patients with DSM-IV schizophrenia (13 Met158/Met158, 17 Val158/Met158, and 12 Val158/Val158). Subjects were studied with functional magnetic resonance imaging while performing a verbal fluency task, with performance recorded online. Main effects of genotype and diagnosis and their interaction on cortical activation and functional connectivity were assessed using SPM5. Results: In the right peri-Sylvian cortex, the Met158 allele of the COMT Val158Met polymorphism was associated with greater activation than the Val158 allele in control subjects; the converse applied in patients (Z = 4.3; false discovery rate p = .04). There was also a strong trend for a group × genotype interaction on functional connectivity between this right peri-Sylvian region and the left anterior insula/operculum (Z = 3.4; p < .001, uncorrected). These findings were independent of between-group differences in task performance, medication, demographic factors, or IQ. Conclusions: Frontotemporal function during verbal generation is modulated by variation in COMT genotype. This effect is altered in schizophrenia, which may reflect the perturbation of central dopamine function associated with the disorder. [Copyright &y& Elsevier]

Abstract: Human adults can assess the number of objects in a set (numerosity) by approximate estimation or by exact counting. There is evidence suggesting that numerosity estimation depends on a dedicated mechanism that is a-modal and non-verbal. By contrast, counting requires the coordination between the pre-existing numerosity estimation abilities with language and one-to-one correspondence principles. In this paper we investigate with fMRI the neural correlates of numerosity estimation and counting in human adults, using both visual and auditory stimuli. Results show that attending to approximate numerosity correlates with increased activity of a right lateralized fronto-parietal cortical network, and that this activity is independent of the stimuli presentation''s modality. Counting activates additional left prefrontal, parietal, and bilateral premotor areas, again independently from stimulus modality. These results dissociate two neuronal systems that underlie different numerosity judgements. [Copyright &y& Elsevier]

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Recent functional neuroimaging studies are generating novel insights into our knowledge of skilled and disturbed reading. In neurologically normal subjects, a double dissociation in neural activation in response to reading words and pseudowords has been revealed that corresponds to that observed in the comparison of semantic and phonological tasks. In patients with acquired dyslexia, functional imaging is demonstrating re-organisation within the reading system; in developmental dyslexia, functional imaging is being used to identify the impact of rehabilitation. Together, these findings have implications for cognitive models of reading that have previously relied on input from behavioural data. [Copyright &y& Elsevier]

Motivated by an energy efficient building application, we want to optimize a quadratic cost functional subject to the Boussinesq approximation of the Navier-Stokes equations and to bilateral state and control constraints. Since the computation of such an optimal solution is numerically costly, we design an efficient strategy to compute a sub-optimal (but applicationally acceptable) solution with significantly reduced computational effort. We employ an economic Model Predictive Control (MPC) strategy to obtain a feedback control. The MPC sub-problems are based on a linear-quadratic optimal control problem subjected to mixed control and state constraints and a convection-diffusion equation, reduced with proper orthogonal decomposition. To solve each sub-problem, we apply a primal-dual active set strategy. The method can be fully parallelized, which enables the solution of large problems with real-world parameters. [ABSTRACT FROM AUTHOR]

Abstract Background Cognitive dysfunction is one of the most prominent characteristics of psychiatric disorders. Currently, the neural correlates of cognitive dysfunction across psychiatric disorders are poorly understood. The aim of this study was to investigate functional connectivity and structural perturbations across psychiatric diagnoses in three neurocognitive networks of interest: the default mode network (DMN), the frontoparietal network (FPN), and the salience network (SN). Methods We performed meta-analyses of resting-state functional magnetic resonance imaging whole-brain seed-based functional connectivity in 8298 patients (involving eight disorders) and 8165 healthy control subjects and a voxel-based morphometry analysis of structural magnetic resonance imaging data in 14,027 patients (involving eight disorders) and 14,504 healthy control subjects. To aid the interpretation of the results, we examined neurocognitive function in 776 healthy participants from the Human Connectome Project. Results We found that the three neurocognitive networks of interest were characterized by shared alterations of functional connectivity architecture across psychiatric disorders. More specifically, hypoconnectivity was expressed between the DMN and ventral SN and between the SN and FPN, whereas hyperconnectivity was evident between the DMN and FPN and between the DMN and dorsal SN. This pattern of network alterations was associated with gray matter reductions in patients and was localized in regions that subserve general cognitive performance. Conclusions This study is the first to provide meta-analytic evidence of common alterations of functional connectivity within and between neurocognitive networks. The findings suggest a shared mechanism of network interactions that may associate with the generalized cognitive deficits observed in psychiatric disorders. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel process scheme for methanol and ammonia production from chemical looping gases. • A final ammonia and methanol production of 910 kg/h and 174 kg/h is achieved. • The LCOAM increases from 0.59 €/kg at 0.01 €/kWh to 1.64 €/kg at 0.13 €/kWh. • Specific emissions of 0.017 kg CO2 /kg prd compared to 0.24 kg CO2 /kg CH3OH and 1.66 kg CO2 /kg NH3 of conventional processes. • Cost competitivity with the electrolytic production of CH 3 OH and NH 3 (separately) was observed. In this work, a techno-economic analysis on a novel plant configuration achieving the combined production of ammonia and methanol through chemical looping has been carried out. The innovative process presents advantages in terms of reduced dependency on market price fluctuations, thanks to the combined production of two chemicals, and optimal utilization of the chemical looping gases. The chemical looping plant is fed with recycled high density polyethylene to enhance the carbon circularity of the process. In this case, part of the captured CO 2 is employed for methanol production along with hydrogen from chemical looping, while hydrogen from electrolysis is used for ammonia production by reaction with nitrogen from the air reactor. Renewable electric energy supply ensures a carbon free power to fuel conversion. Several sensitivity analyses were carried out to assess the optimum process parameters combination, i.e. fuel flow rate, steam flow rate, oxygen carrier inlet temperature. The final production rate is divided between 174 kg/h of methanol and 910 kg/h of ammonia. An economic analysis was then carried out. A capital cost of 27 M€ and an operating cost of 3 M€/y were computed. Sensitivity analyses on the impact of the electricity input cost, the electrolytic oxygen selling price, the electrolyser capital cost and the internal rate of return were carried out. The electricity demand was discovered to impact for the 68% of the total operating costs. For an electricity cost of 0.03 €/kWh, oxygen selling price of 0.07 €/kg O2 and internal rate of return of 8%, a final products cost of 0.76 €/kg was then determined. The process achieves specific CO 2 emissions of 0.017 kg CO2 /kg prd , which is significantly lower than the traditional processes (0.24 kg CO2 /kg CH3OH and 1.66 kg CO2 /kg NH3), and an energy intensity of 36 GJ/t prd. The final selling price of the products is still not competitive with the traditional processes but is comparable with ammonia production from electrolysis and air separation and methanol production from electrolysis and direct air capture. [ABSTRACT FROM AUTHOR]