Boundary completion is automatic and dissociable from shape discrimination

Normal visual perception readily overcomes suboptimal or degraded viewing conditions through perceptual filling-in processes, enhancing object recognition and discrimination abilities. This study used visual evoked potential (VEP) recordings in conjunction with electrical neuroimaging analyses to determine the spatiotemporal brain dynamics of boundary completion and shape discrimination processes in healthy humans performing the so-called "thin/fat" discrimination task (Ringach and Shapley, 1996) with stimuli producing illusory contours. First, results suggest that boundary completion processes occur independent of subjects' accuracy on the discrimination task. Modulation of the VEP to the presence versus absence of illusory contours [the IC effect (Murray et al., 2002)] was indistinguishable in terms of response magnitude and scalp topography over the 124-186 ms poststimulus period, regardless of whether task performance was correct. This suggests that failure on this discrimination task is not primarily a consequence of failed boundary completion. Second, the electrophysiological correlates of thin/fat shape discrimination processes are temporally dissociable from those of boundary completion, occurring during a substantially later phase of processing (approximately 330-406 ms). The earlier IC effect was unaffected by whether the perceived contour produced a thin or fat shape. In contrast, later time periods of the VEP modulated according to perceived shape only in the case of stimuli producing illusory contours, but not for control stimuli for which performance was at near-chance levels. Collectively, these data provide further support for a multistage model of object processing under degraded viewing conditions

Translating Glutamate: From Pathophysiology to Treatment

The neurotransmitter glutamate is the primary excitatory neurotransmitter in mammalian brain and is responsible for most corticocortical and corticofugal neurotransmission. Disturbances in glutamatergic function have been implicated in the pathophysiology of several neuropsychiatric disorders—including schizophrenia, drug abuse and addiction, autism, and depression—that were until recently poorly understood. Nevertheless, improvements in basic information regarding these disorders have yet to translate into Food and Drug Administration–approved treatments. Barriers to translation include the need not only for improved compounds but also for improved biomarkers sensitive to both structural and functional target engagement and for improved translational models. Overcoming these barriers will require unique collaborative arrangements between pharma, government, and academia. Here, we review a recent Institute of Medicine–sponsored meeting, highlighting advances in glutamatergic theories of neuropsychiatric illness as well as remaining barriers to treatment development.National Institute of Mental Health (U.S.) (grant R37MH49334)National Institute of Mental Health (U.S.) (Intramural Research Program)National Institute of Mental Health (U.S.) (R01DA03383)National Institute of Mental Health (U.S.) (P50MH086385)National Institutes of Health (U.S.)FRAXA Research FoundationHoward Hughes Medical InstituteSimons Foundatio

Dysconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring

Over the last 2 decades, a large number of neurophysiological and neuroimaging studies of patients with schizophrenia have furnished in vivo evidence for dysconnectivity, ie, abnormal functional integration of brain processes. While the evidence for dysconnectivity in schizophrenia is strong, its etiology, pathophysiological mechanisms, and significance for clinical symptoms are unclear. First, dysconnectivity could result from aberrant wiring of connections during development, from aberrant synaptic plasticity, or from both. Second, it is not clear how schizophrenic symptoms can be understood mechanistically as a consequence of dysconnectivity. Third, if dysconnectivity is the primary pathophysiology, and not just an epiphenomenon, then it should provide a mechanistic explanation for known empirical facts about schizophrenia. This article addresses these 3 issues in the framework of the dysconnection hypothesis. This theory postulates that the core pathology in schizophrenia resides in aberrant N-methyl-D-aspartate receptor (NMDAR)–mediated synaptic plasticity due to abnormal regulation of NMDARs by neuromodulatory transmitters like dopamine, serotonin, or acetylcholine. We argue that this neurobiological mechanism can explain failures of self-monitoring, leading to a mechanistic explanation for first-rank symptoms as pathognomonic features of schizophrenia, and may provide a basis for future diagnostic classifications with physiologically defined patient subgroups. Finally, we test the explanatory power of our theory against a list of empirical facts about schizophrenia

Contribution of Cystine-Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystine–glutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystine–glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex, an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial t-maze task, and this effect was also reversed by N-acetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystine–glutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystine–glutamate exchange and group II mGluR activation. Finally, protein levels from postmortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystine–glutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystine–glutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP

Emotion-Related Visual Mismatch Responses in Schizophrenia: Impairments and Correlations with Emotion Recognition.

BACKGROUND AND OBJECTIVES:Mismatch negativity (MMN) is an event-related potential (ERP) measure of preattentional sensory processing. While deficits in the auditory MMN are robust electrophysiological findings in schizophrenia, little is known about visual mismatch response and its association with social cognitive functions such as emotion recognition in schizophrenia. Our aim was to study the potential deficit in the visual mismatch response to unexpected facial emotions in schizophrenia and its association with emotion recognition impairments, and to localize the sources of the mismatch signals. EXPERIMENTAL DESIGN:The sample comprised 24 patients with schizophrenia and 24 healthy control subjects. Controls were matched individually to patients by gender, age, and education. ERPs were recorded using a high-density 128-channel BioSemi amplifier. Mismatch responses to happy and fearful faces were determined in 2 time windows over six regions of interest (ROIs). Emotion recognition performance and its association with the mismatch response were also investigated. PRINCIPAL OBSERVATIONS:Mismatch signals to both emotional conditions were significantly attenuated in patients compared to controls in central and temporal ROIs. Controls recognized emotions significantly better than patients. The association between overall emotion recognition performance and mismatch response to the happy condition was significant in the 250-360 ms time window in the central ROI. The estimated sources of the mismatch responses for both emotional conditions were localized in frontal regions, where patients showed significantly lower activity. CONCLUSIONS:Impaired generation of mismatch signals indicate insufficient automatic processing of emotions in patients with schizophrenia, which correlates strongly with decreased emotion recognition

The impact of cataract surgery on activities and time-use: results from a longitudinal study in Kenya, Bangladesh and the Philippines.

BACKGROUND: Cataract is the leading cause of blindness in the world, and blindness from cataract is particularly common in low-income countries. The aim of this study is to explore the impact of cataract surgery on daily activities and time-use in Kenya, Bangladesh and the Philippines. METHODS/PRINCIPAL FINDINGS: A multi-centre intervention study was conducted in three countries. Time-use data were collected through interview from cases aged >or=50 years with visually impairing cataract (VA or=6/18). Cases were offered free/subsidized cataract surgery. Approximately one year later participants were re-interviewed about time-use. At baseline across the three countries there were 651 cases and 571 controls. Fifty-five percent of cases accepted surgery. Response rate at follow up was 84% (303 out of 361) for operated cases, and 80% (459 out of 571) for controls. At baseline, cases were less likely to carry out and spent less time on productive activities (paid and non-paid work) and spent more time in "inactivity" compared to controls. Approximately one year after cataract surgery, operated cases were more likely to undertake productive activities compared to baseline (Kenya from 55% to 88%; Bangladesh 60% to 95% and Philippines 81% to 94%, p<0.001) and mean time spent on productive activities increased by one-two hours in each setting (p<0.001). Time spent in "inactivity" in Kenya and Bangladesh decreased by approximately two hours (p<0.001). Frequency of reported assistance with activities was more than halved in each setting (p<0.001). CONCLUSIONS/SIGNIFICANCE: The empirical evidence provided by this study of increased time spent on productive activities, reduced time in inactivity and reduced assistance following cataract surgery among older adults in low-income settings has positive implications for well-being and inclusion, and supports arguments of economic benefit at the household level from cataract surgery

Contributions of early cortical processing and reading ability to functional status in individuals at clinical high risk for psychosis

Background: There is a growing recognition that individuals at clinical high risk need intervention for functional impairments, along with emerging psychosis, as the majority of clinical high risk (CHR) individuals show persistent deficits in social and role functioning regardless of transition to psychosis. Recent studies have demonstrated reduced reading ability as a potential cause of functional disability in schizophrenia, related to underlying deficits in generation of mismatch negativity (MMN). The present study extends these findings to subjects at CHR. Methods: The sample consisted of 34 CHR individuals and 33 healthy comparison subjects (CNTLs) from the Recognition and Prevention (RAP) Program at the Zucker Hillside Hospital in New York. At baseline, reading measures were collected, along with MMN to pitch, duration, and intensity deviants, and measures of neurocognition, and social and role (academic/work) functioning. Results: CHR subjects showed impairments in reading ability, neurocognition, and MMN generation, relative to CNTLs. Lower-amplitude MMN responses were correlated with worse reading ability, slower processing speed, and poorer social and role functioning. However, when entered into a simultaneous regression, only reduced responses to deviance in sound duration and volume predicted poor social and role functioning, respectively. Conclusions: Deficits in reading ability exist even prior to illness onset in schizophrenia and may represent a decline in performance from prior abilities. As in schizophrenia, deficits are related to impaired MMN generation, suggesting specific contributions of sensory-level impairment to neurocognitive processes related to social and role function. (C) 2015 Elsevier B.V. All rights reserved

Intellectual Property, Open Science and Research Biobanks

In biomedical research and translational medicine, the ancient war between exclusivity (private control over information) and access to information is proposing again on a new battlefield: research biobanks. The latter are becoming increasingly important (one of the ten ideas changing the world, according to Time magazine) since they allow to collect, store and distribute in a secure and professional way a critical mass of human biological samples for research purposes. Tissues and related data are fundamental for the development of the biomedical research and the emerging field of translational medicine: they represent the “raw material” for every kind of biomedical study. For this reason, it is crucial to understand the boundaries of Intellectual Property (IP) in this prickly context. In fact, both data sharing and collaborative research have become an imperative in contemporary open science, whose development depends inextricably on: the opportunities to access and use data, the possibility of sharing practices between communities, the cross-checking of information and results and, chiefly, interactions with experts in different fields of knowledge. Data sharing allows both to spread the costs of analytical results that researchers cannot achieve working individually and, if properly managed, to avoid the duplication of research. These advantages are crucial: access to a common pool of pre-competitive data and the possibility to endorse follow-on research projects are fundamental for the progress of biomedicine. This is why the "open movement" is also spreading in the biobank's field. After an overview of the complex interactions among the different stakeholders involved in the process of information and data production, as well as of the main obstacles to the promotion of data sharing (i.e., the appropriability of biological samples and information, the privacy of participants, the lack of interoperability), we will firstly clarify some blurring in language, in particular concerning concepts often mixed up, such as “open source” and “open access”. The aim is to understand whether and to what extent we can apply these concepts to the biomedical field. Afterwards, adopting a comparative perspective, we will analyze the main features of the open models – in particular, the Open Research Data model – which have been proposed in literature for the promotion of data sharing in the field of research biobanks. After such an analysis, we will suggest some recommendations in order to rebalance the clash between exclusivity - the paradigm characterizing the evolution of intellectual property over the last three centuries - and the actual needs for access to knowledge. We argue that the key factor in this balance may come from the right interaction between IP, social norms and contracts. In particular, we need to combine the incentives and the reward mechanisms characterizing scientific communities with data sharing imperative

Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A "central hub" in schizophrenia pathophysiology?

Accumulating evidence points to altered GABAergic parvalbumin-expressing interneurons and impaired myelin/axonal integrity in schizophrenia. Both findings could be due to abnormal neurodevelopmental trajectories, affecting local neuronal networks and long-range synchrony and leading to cognitive deficits. In this review, we present data from animal models demonstrating that redox dysregulation, neuroinflammation and/or NMDAR hypofunction (as observed in patients) impairs the normal development of both parvalbumin interneurons and oligodendrocytes. These observations suggest that a dysregulation of the redox, neuroimmune, and glutamatergic systems due to genetic and early-life environmental risk factors could contribute to the anomalies of parvalbumin interneurons and white matter in schizophrenia, ultimately impacting cognition, social competence, and affective behavior via abnormal function of micro- and macrocircuits. Moreover, we propose that the redox, neuroimmune, and glutamatergic systems form a "central hub" where an imbalance within any of these "hub" systems leads to similar anomalies of parvalbumin interneurons and oligodendrocytes due to the tight and reciprocal interactions that exist among these systems. A combination of vulnerabilities for a dysregulation within more than one of these systems may be particularly deleterious. For these reasons, molecules, such as N-acetylcysteine, that possess antioxidant and anti-inflammatory properties and can also regulate glutamatergic transmission are promising tools for prevention in ultra-high risk patients or for early intervention therapy during the first stages of the disease