Working memory in schizophrenia: dynamic visuo-spatial information processing

Working memory, commonly defined as the ability to hold mental representations on line transiently and to manipulate these representations, is known to be a core deficit in schizophrenia. The aim of the present study was to investigate the visuo-spatial component of the working memory in schizophrenia, and more precisely to what extent the dynamic visuo-spatial information processing is impaired in schizophrenia patients. For this purpose we used a computerized paradigm in which 29 patients with schizophrenia (DSMIV, Diagnostic Interview for Genetic Studies) and 29 age and sex matched control subjects (DIGS) had to memorize a plane moving across the computer screen and to identify the observed trajectory among 9 plots proposed together. Each trajectory could be seen max. 3 times if needed. The results showed no difference between schizophrenia patients and controls regarding the number of correct trajectory identified after the first presentation. However, when we determine the mean number of correct trajectories on the basis of 3 trials, we observed that schizophrenia patients are significantly less performant than controls (Mann-Whitney, p _ 0.002). These findings suggest that, although schizophrenia patients are able to memorize some dynamic trajectories as well as controls, they do not profit from the repetition of the trajectory presentation. These findings are congruent with the hypothesis that schizophrenia could induce an unbalance between local and global information processing: the patients may be able to focus on details of the trajectory which could allow them to find the right target (bottom-up processes), but may show difficulty to refer to previous experience in order to filter incoming information (top-down processes) and enhance their visuo-spatial working memory abilities.

Attribution d'intentions hostiles et intentions comportementales agressives dans un contexte intergroupes

We conducted two experiments to demonstrate the relevance of group membership (in-group vs. out-group) in the processing of conflictual social interactions as described by Dodge (1980; Dodge, Pettit, Mcclaskey, & Brown, 1986). In the first study, we highlighted the impact of group membership on the attribution of hostile intents and on reactions to a provocation. In the second study we found that the impact of group membership on aggressive reaction intents is moderated by the status of people in the interaction, and that this effect is partially mediated by attribution of hostile intents. We conclude by stressing the necessity to integrate intergroup dynamics in the social information processing model elaborated by Dodge.

Visuo-spatial processing in a dynamic and a static working memory paradigm in schizophrenia.

Recent findings suggest that the visuo-spatial sketchpad (VSSP) may be divided into two sub-components processing dynamic or static visual information. This model may be useful to elucidate the confusion of data concerning the functioning of the VSSP in schizophrenia. The present study examined patients with schizophrenia and matched controls in a new working memory paradigm involving dynamic (the Ball Flight Task - BFT) or static (the Static Pattern Task - SPT) visual stimuli. In the BFT, the responses of the patients were apparently based on the retention of the last set of segments of the perceived trajectory, whereas control subjects relied on a more global strategy. We assume that the patients' performances are the result of a reduced capacity in chunking visual information since they relied mainly on the retention of the last set of segments. This assumption is confirmed by the poor performance of the patients in the static task (SPT), which requires a combination of stimulus components into object representations. We assume that the static/dynamic distinction may help us to understand the VSSP deficits in schizophrenia. This distinction also raises questions about the hypothesis that visuo-spatial working memory can simply be dissociated into visual and spatial sub-components.

Representing diffusion MRI in 5D for segmentation of white matter tracts with a level set method.

We present a method for segmenting white matter tracts from high angular resolution diffusion MR. images by representing the data in a 5 dimensional space of position and orientation. Whereas crossing fiber tracts cannot be separated in 3D position space, they clearly disentangle in 5D position-orientation space. The segmentation is done using a 5D level set method applied to hyper-surfaces evolving in 5D position-orientation space. In this paper we present a methodology for constructing the position-orientation space. We then show how to implement the standard level set method in such a non-Euclidean high dimensional space. The level set theory is basically defined for N-dimensions but there are several practical implementation details to consider, such as mean curvature. Finally, we will show results from a synthetic model and a few preliminary results on real data of a human brain acquired by high angular resolution diffusion MRI.

Do pseudo-absence selection strategies influence species distribution models and their predictions? An information-theoretic approach based on simulated data

Background Multiple logistic regression is precluded from many practical applications in ecology that aim to predict the geographic distributions of species because it requires absence data, which are rarely available or are unreliable. In order to use multiple logistic regression, many studies have simulated "pseudo-absences" through a number of strategies, but it is unknown how the choice of strategy influences models and their geographic predictions of species. In this paper we evaluate the effect of several prevailing pseudo-absence strategies on the predictions of the geographic distribution of a virtual species whose "true" distribution and relationship to three environmental predictors was predefined. We evaluated the effect of using a) real absences b) pseudo-absences selected randomly from the background and c) two-step approaches: pseudo-absences selected from low suitability areas predicted by either Ecological Niche Factor Analysis: (ENFA) or BIOCLIM. We compared how the choice of pseudo-absence strategy affected model fit, predictive power, and information-theoretic model selection results. Results Models built with true absences had the best predictive power, best discriminatory power, and the "true" model (the one that contained the correct predictors) was supported by the data according to AIC, as expected. Models based on random pseudo-absences had among the lowest fit, but yielded the second highest AUC value (0.97), and the "true" model was also supported by the data. Models based on two-step approaches had intermediate fit, the lowest predictive power, and the "true" model was not supported by the data. Conclusion If ecologists wish to build parsimonious GLM models that will allow them to make robust predictions, a reasonable approach is to use a large number of randomly selected pseudo-absences, and perform model selection based on an information theoretic approach. However, the resulting models can be expected to have limited fit.

Intelligence-led crime scene processing. Part I : Forensic intelligence.

Forensic science is generally defined as the application of science to address questions related to the law. Too often, this view restricts the contribution of science to one single process which eventually aims at bringing individuals to court while minimising risk of miscarriage of justice. In order to go beyond this paradigm, we propose to refocus the attention towards traces themselves, as remnants of a criminal activity, and their information content. We postulate that traces contribute effectively to a wide variety of other informational processes that support decision making inmany situations. In particular, they inform actors of new policing strategies who place the treatment of information and intelligence at the centre of their systems. This contribution of forensic science to these security oriented models is still not well identified and captured. In order to create the best condition for the development of forensic intelligence, we suggest a framework that connects forensic science to intelligence-led policing (part I). Crime scene attendance and processing can be envisaged within this view. This approach gives indications abouthowto structure knowledge used by crime scene examiners in their effective practice (part II).

Auditory spatio-temporal brain dynamics and their consequences for multisensory interactions in humans.

Recent multisensory research has emphasized the occurrence of early, low-level interactions in humans. As such, it is proving increasingly necessary to also consider the kinds of information likely extracted from the unisensory signals that are available at the time and location of these interaction effects. This review addresses current evidence regarding how the spatio-temporal brain dynamics of auditory information processing likely curtails the information content of multisensory interactions observable in humans at a given latency and within a given brain region. First, we consider the time course of signal propagation as a limitation on when auditory information (of any kind) can impact the responsiveness of a given brain region. Next, we overview the dual pathway model for the treatment of auditory spatial and object information ranging from rudimentary to complex environmental stimuli. These dual pathways are considered an intrinsic feature of auditory information processing, which are not only partially distinct in their associated brain networks, but also (and perhaps more importantly) manifest only after several tens of milliseconds of cortical signal processing. This architecture of auditory functioning would thus pose a constraint on when and in which brain regions specific spatial and object information are available for multisensory interactions. We then separately consider evidence regarding mechanisms and dynamics of spatial and object processing with a particular emphasis on when discriminations along either dimension are likely performed by specific brain regions. We conclude by discussing open issues and directions for future research.

Mice with chronic GSH deficit display phenotypical anomalies that resemble key aspects of schizophrenia

ABSTRACTSchizophrenia is a major psychiatric disorder occurring with a prevalence of 1% in the worldwide population. It develops progressively with psychosis onset in late adolescence or earlyadulthood. The disorder can take many different facets and has a highly diffuse anddistributed neuropathology including deficits in major neurotransmitter systems,myelination, stress regulation, and metabolism. The delayed onset and the heterogeneouspathology suggest that schizophrenia is a developmental disease that arises from interplayof genetic and environmental factors during sensitive periods. Redox dysregulation due to animbalance between pro-oxidants and antioxidant defence mechanisms is among the riskfactors for schizophrenia. Glutathione (GSH) is the major cellular redox regulator andantioxidant. Levels of GSH are decreased in cerebrospinal fluid, prefrontal cortex and postmortemstriatum of schizophrenia patients. Moreover, polymorphisms of the key GSHsynthesizingenzyme, glutamate-cysteine ligase, modifier (GCLM) subunit, are associatedwith the disease, suggesting that GSH deficit is of genetic origin. Here we used miceknockout (KO) for the GCLM gene, which display chronic GSH deficit (~70 to 80% decrease)to investigate the direct link between redox dysregulation and schizophrenia. Accordingly,we evaluated whether GCLM KO compared to normal wildtype mice display behavioralchanges that relate to schizophrenia symptoms and whether their brains showmorphological, functional or metabolic alterations that resemble those in patients.Moreover, we exposed pubertal GCLM mice to repeated mild stress and measured theirhormonal and behavioral stress reactivity. Our data show that chronic GSH deficit isassociated with altered emotion- and stress-related behaviors, deficient prepulse inhibition,pronounced amphetamine-induced hyperlocomotion but normal spatial learning andworking memory. These changes represent important schizophrenia endophenotypes.Moreover, this particular pattern of change indicates impairment of the ventralhippocampus (VH) and related circuitry as opposed to the dorsal hippocampus (DH), which isimplicated in spatial information processing. This is consistent with a selective deficit ofparvalbumin positive interneurons and gamma oscillation in the VH but not DH. Increasedlevels of circulating stress hormones in KO mice following pubertal stress corroborate VHdysfunction as it is involved in negative feedback control of the stress response. VHstructural and functional deficits are frequently found in the schizophrenic brain. Metabolicevaluation of the developing GCLM KO anterior cortex using in vivo magnetic resonancespectroscopy revealed elevated glutamine (Gln), glutamate (Glu), Gln/Glu and N-acetylaspartate(NAA) during the pre-pubertal period. Similar changes are reported in earlyschizophrenia. Overall, we observe phenotypic anomalies in GSH deficient GCLM KO micethat correspond to major schizophrenia endophenotypes. This supports an important rolefor redox dysregulation in schizophrenia and validates the GCLM KO mouse as model for thedisease. Moreover, our results indicate that puberty may be a sensitive period for redoxsensitivechanges highliting the importance of early intervention. Gln, Gln/Glu, Glu and NAAmay qualify as early metabolic biomarkers to identify young at-risk individuals. Since chronictreatment with NAC normalized most metabolic changes in GCLM KO mice, NAC may be oneadjunct treatment of choice for early intervention in patients.RESUMELa schizophrénie est une maladie psychiatrique majeure avec une prévalence de 1% dans lapopulation. Son développement est progressif, les premières psychoses apparaissant àl'adolescence ou au début de l'âge adulte. La maladie a plusieurs présentations et uneneuropathologie étendue, qui inclut des déficits neurochimiques, métaboliques, de lamyélination et de la régulation du stress. L'émergence tardive et l'hétérogénéité de lapathologie suggèrent que la schizophrénie est une maladie développementale, favorisée pardes facteurs génétiques et environnementaux durant des périodes sensibles. La dérégulationrédox, due à un déséquilibre entre facteurs pro-oxidantes et défenses anti-oxidantes,constitue un facteur de risque. Le glutathion (GSH) est le principal régulateur rédox et antioxidantdes cellules, ses taux sont diminués dans le liquide céphalorachidien, le cortexpréfrontal et le striatum de patients. De plus, des variations du gène codant la sous-unitémodulatrice (GCLM) de la glutamate-cystéine ligase, enzyme de synthèse du GSH, sontassociés la maladie, suggérant que le déficit observé chez les patients est d'originegénétique. Nous avons donc utilisé des souris ayant une délétion du gène GCLM (KO), quiont un déficit chronique en GSH (70-80%), afin d'étudier le lien entre une dérégulation rédoxet la schizophrénie. Nous avons évalué si ces souris présentent des altérationscomportementales analogues aux symptômes de la maladie, et des modificationsstructurelles, fonctionnelles et métaboliques au niveau du cerveau, ressemblant à celles despatients. De plus, nous avons soumis les souris à des stresses modérés durant la puberté,puis mesuré les réponses hormonales et comportementales. Les animaux présentent undéficit pré-attentionnel du traitement des informations moto-sensorielles, un déficit pourcertains apprentissages, une réponse accrue à l'amphétamine, mais leurs mémoires spatialeet de travail sont préservées. Ces atteintes comportementales sont analogues à certainsendophénotypes de la schizophrénie. De plus, ces changements comportementaux sontlargement expliqués par une perturbation morphologique et fonctionnelle de l'hippocampeventral (HV). Ainsi, nous avons observé un déficit sélectif des interneurones immunoréactifsà la parvalbumine et une désynchronisation neuronale dans l'HV. L'hippocampe dorsal,impliqué dans l'orientation spatiale, demeure en revanche intact. L'augmentationd'hormones de stress dans le sang des souris KO suite à un stress prépubertal soutien aussil'hypothèse d'une dysfonction de l'HV, connu pour moduler ce type de réponse. Des déficitsstructurels et fonctionnels dans l'hippocampe antérieur (ventral) ont d'ailleurs été rapportéschez des patients schizophrènes. Par de résonance magnétique, nous avons également suivile profil métabolique du le cortex antérieur au cours du développement postnatal des sourisKO. Ces mesures ont révélé des taux élevés de glutamine (Gln), glutamate (Glu), du ratioGln/Glu, et de N-acétyl-aspartate (NAA) durant la période prépubertale. Des altérationssimilaires sont décrites chez les patients durant la phase précoce. Nous avons donc révélédes anomalies phénotypiques chez les souris GCLM KO qui reflètent certainsendophénotypes de la schizophrénie. Nos résultats appuient donc le rôle d'une dérégulationrédox dans l'émergence de la maladie et le potentiel des souris KO comme modèle. De plus,cette étude met en évidence la puberté comme période particulièrement sensible à unedérégulation rédox, renforçant l'importance d'une intervention thérapeutique précoce. Dansce cadre, Gln, Gln/Glu, Glu and NAA seraient des biomarqueurs clés pour identifier de jeunesindividus à risque. De part son efficacité dans notre modèle, NAC pourrait être unesubstance de choix dans le traitement précoce des patients.

Cooperation versus competition effects on information sharing and use in group decision making

Information processing in groups has long been seen as a cooperative process. In contrast with this assumption, group members were rarely found to behave cooperatively: They withhold unshared information and stick to initial incorrect decisions. In the present article, we examined how group members' cooperative and competitivemotives impact on group information processing and propose that information sharing and use in groups could be seen as strategic behavior. We reviewed the latest developments in the literature investigating different forms of strategic information processing and their underlying mechanisms. This review suggests that explicit cooperative goals are needed for effective group decision-making.

Men perform comparably to women in a perspective taking task after administration of intranasal oxytocin but not after placebo

Oxytocin (OT) is thought to play an important role in human interpersonal information processing and behavior. By inference, OT should facilitate empathic responding, i.e. the ability to feel for others and to take their perspective. In two independent double-blind, placebo-controlled between-subjects studies, we assessed the effect of intranasally administered OT on affective empathy and perspective taking, whilst also examining potential sex differences (e.g., women being more empathic than men). In study 1, we provided 96 participants (48 men) with an empathy scenario and recorded self reports of empathic reactions to the scenario, while in study 2, a sample of 120 individuals (60 men) performed a computerized implicit perspective taking task. Whilst results from Study 1 showed no influence of OT on affective empathy, we found in Study 2 that OT exerted an effect on perspective taking ability in men. More specifically, men responded faster than women in the placebo group but they responded as slowly as women in the OT group. We conjecture that men in the OT group adopted a social perspective taking strategy, such as did women in both groups, but not men in the placebo group. On the basis of results across both studies, we suggest that self-report measures (such as used in Study 1) might be less sensitive to OT effects than more implicit measures of empathy such as that used in Study 2. If these assumptions are confirmed, one could infer that OT effects on empathic responses are more pronounced in men than women, and that any such effect is best studied using more implicit measures of empathy rather than explicit self-report measures.

What do we know about gliotransmitter release from astrocytes?

Astrocytes participate in information processing by actively modulating synaptic properties via gliotransmitter release. Various mechanisms of astrocytic release have been reported, including release from storage organelles via exocytosis and release from the cytosol via plasma membrane ion channels and pumps. It is still not fully clear which mechanisms operate under which conditions, but some of them, being Ca(2+)-regulated, may be physiologically relevant. The properties of Ca(2+)-dependent transmitter release via exocytosis or via ion channels are different and expected to produce different extracellular transmitter concentrations over time and to have distinct functional consequences. The molecular aspects of these two release pathways are still under active investigation. Here, we discuss the existing morphological and functional evidence in support of either of them. Transgenic mouse models, specific antagonists and localization studies have provided insight into regulated exocytosis, albeit not in a systematic fashion. Even more remains to be uncovered about the details of channel-mediated release. Better functional tools and improved ultrastructural approaches are needed in order fully to define specific modalities and effects of astrocytic gliotransmitter release pathways.

Effects of anxiety on visuospatial pattern discrimination and decision-making processes: what can we learn from brain dynamics ?

Detection and discrimination of visuospatial input involve at least extracting, selecting and encoding relevant information and decision-making processes allowing selecting a response. These two operations are altered, respectively, by attentional mechanisms that change discrimination capacities, and by beliefs concerning the likelihood of uncertain events. Information processing is tuned by the attentional level that acts like a filter on perception, while decision-making processes are weighed by subjective probability of risk. In addition, it has been shown that anxiety could affect the detection of unexpected events through the modification of the level of arousal. Consequently, purpose of this study concerns whether and how decision-making and brain dynamics are affected by anxiety. To investigate these questions, the performance of women with either a high (12) or a low (12) STAI-T (State-Trait Anxiety Inventory, Spielberger, 1983) was examined in a decision-making visuospatial task where subjects have to recognize a target visual pattern from non-target patterns. The target pattern was a schematic image of furniture arranged in such a way as to give the impression of a living room. Non-target patterns were created by either the compression or the dilatation of the distances between objects. Target and non-target patterns were always presented in the same configuration. Preliminary behavioral results show no group difference in reaction time. In addition, visuo-spatial abilities were analyzed trough the signal detection theory for quantifying perceptual decisions in the presence of uncertainty (Green and Swets, 1966). This theory treats detection of a stimulus as a decision-making process determined by the nature of the stimulus and cognitive factors. Astonishingly, no difference in d' (corresponding to the distance between means of the distributions) and c (corresponds to the likelihood ratio) indexes was observed. Comparison of Event-related potentials (ERP) reveals that brain dynamics differ according to anxiety. It shows differences in component latencies, particularly a delay in anxious subjects over posterior electrode sites. However, these differences are compensated during later components by shorter latencies in anxious subjects compared to non-anxious one. These inverted effects seem indicate that the absence of difference in reaction time rely on a compensation of attentional level that tunes cortical activation in anxious subjects, but they have to hammer away to maintain performance.

Efficient gene delivery and selective transduction of astrocytes in the mammalian brain using viral vectors.

Astrocytes are now considered as key players in brain information processing because of their newly discovered roles in synapse formation and plasticity, energy metabolism and blood flow regulation. However, our understanding of astrocyte function is still fragmented compared to other brain cell types. A better appreciation of the biology of astrocytes requires the development of tools to generate animal models in which astrocyte-specific proteins and pathways can be manipulated. In addition, it is becoming increasingly evident that astrocytes are also important players in many neurological disorders. Targeted modulation of protein expression in astrocytes would be critical for the development of new therapeutic strategies. Gene transfer is valuable to target a subpopulation of cells and explore their function in experimental models. In particular, viral-mediated gene transfer provides a rapid, highly flexible and cost-effective, in vivo paradigm to study the impact of genes of interest during central nervous system development or in adult animals. We will review the different strategies that led to the recent development of efficient viral vectors that can be successfully used to selectively transduce astrocytes in the mammalian brain.

Adaptive filtering methods for identifying cross-frequency couplings in human EEG.

Oscillations have been increasingly recognized as a core property of neural responses that contribute to spontaneous, induced, and evoked activities within and between individual neurons and neural ensembles. They are considered as a prominent mechanism for information processing within and communication between brain areas. More recently, it has been proposed that interactions between periodic components at different frequencies, known as cross-frequency couplings, may support the integration of neuronal oscillations at different temporal and spatial scales. The present study details methods based on an adaptive frequency tracking approach that improve the quantification and statistical analysis of oscillatory components and cross-frequency couplings. This approach allows for time-varying instantaneous frequency, which is particularly important when measuring phase interactions between components. We compared this adaptive approach to traditional band-pass filters in their measurement of phase-amplitude and phase-phase cross-frequency couplings. Evaluations were performed with synthetic signals and EEG data recorded from healthy humans performing an illusory contour discrimination task. First, the synthetic signals in conjunction with Monte Carlo simulations highlighted two desirable features of the proposed algorithm vs. classical filter-bank approaches: resilience to broad-band noise and oscillatory interference. Second, the analyses with real EEG signals revealed statistically more robust effects (i.e. improved sensitivity) when using an adaptive frequency tracking framework, particularly when identifying phase-amplitude couplings. This was further confirmed after generating surrogate signals from the real EEG data. Adaptive frequency tracking appears to improve the measurements of cross-frequency couplings through precise extraction of neuronal oscillations.

Essential Bacillus subtilis genes.

To estimate the minimal gene set required to sustain bacterial life in nutritious conditions, we carried out a systematic inactivation of Bacillus subtilis genes. Among approximately 4,100 genes of the organism, only 192 were shown to be indispensable by this or previous work. Another 79 genes were predicted to be essential. The vast majority of essential genes were categorized in relatively few domains of cell metabolism, with about half involved in information processing, one-fifth involved in the synthesis of cell envelope and the determination of cell shape and division, and one-tenth related to cell energetics. Only 4% of essential genes encode unknown functions. Most essential genes are present throughout a wide range of Bacteria, and almost 70% can also be found in Archaea and Eucarya. However, essential genes related to cell envelope, shape, division, and respiration tend to be lost from bacteria with small genomes. Unexpectedly, most genes involved in the Embden-Meyerhof-Parnas pathway are essential. Identification of unknown and unexpected essential genes opens research avenues to better understanding of processes that sustain bacterial life.