Segregation, connectivity, and gradients of deactivation in neural correlates of evidence in social decision making.

Functional imaging studies of sensory decision making have detected a signal associated with evidence for decisions that is consistent with data from single-cell recordings in laboratory animals. However, the generality of this finding and its implications on our understanding of the organization of the fMRI signal are not clear. In the present functional imaging study, we investigated decisions in an elementary social cognition domain to identify the neural correlates of evidence, their segregation, connectivity, and their relationship to task deactivations. Besides providing data in support of an evidence-related signal in a social cognition task, we were interested in embedding these neural correlates in models of supramodal associative cortex placed at the top of a hierarchy of processing areas. Participants were asked to decide which of two depicted individuals was saddest based on information rich in sensory features (facial expressions) or through contextual cues suggesting the mental state of others (stylized drawings of mourning individuals). The signal associated with evidence for the decision was located in two distinct networks differentially recruited depending on the information type. Using the largest peaks of the signal associated with evidence as seeds in a database of connectivity data, these two networks were retrieved. Furthermore, the hubs of these networks were located near or along a ribbon of cortex located between task activations and deactivations between areas affected by perceptual priming and the deactivated areas of the default network system. In associative cortex, these findings suggest gradients of progressive relative deactivation as a possible neural correlate of the cortical organization envisaged by structural models of cortical organization and by predictive coding theories of cortical function.

Adaptation of the Scrambled-Sentences Task to Assess "Shattered Assumptions:" Construction of the Test and Investigation of Neural Substrates in an fMRI Study.

BACKGROUND: Increasing recognition is being given to the importance of cognitions observed in posttraumatic conditions. These cognitions may reflect the activation of negative schemas. The aim of this work was to evaluate the feasibility of the scrambled-sentences task (SST) to assess individual differences in attributions commonly observed after traumas. Originally developed to assess the tendency to activate negative cognitions in individuals predisposed to depression, the SST is a laboratory task the outcome of which has been shown to predict depression relapse and is associated with depressiveness. SAMPLING AND METHODS: We used content from self-rating scales for assessment of the activation of trauma-related schemas to develop a trauma-related SST and evaluated its performance in a behavioral study (n = 43) and a functional neuroimaging study (n = 20). RESULTS: In the healthy sample in which we tested it, the trauma-related SST was strongly associated with individual differences in negative affect (scores in depressiveness and neuroticism scales) as well as with the scores on trauma-related cognition scales. However, we failed to detect a clear specificity of trauma-related cognitions in correlations with scores on the trauma-related scales in the healthy participants. The neuroimaging data demonstrated activation of a ventral network of areas that included the perisylvian/temporal cortex and the peri-cingular cortex in handling trauma-related relative to neutral material, replicating previous neuroimaging studies of the SST. CONCLUSION: The shattered-assumptions SST demonstrated strong associations with individual differences in all of the rating scales used in the study, suggesting its usefulness in capturing aspects of affective psychopathology. The neuroimaging study confirmed the capacity of this task to elicit specific activations. In future studies, evaluation of the conditions in which these neural substrates are active may shed light on the mechanism of schema selection.

Deconstructing the differences: a comparison of GBD 2010 and CHERG's approach to estimating the mortality burden of diarrhea, pneumonia, and their etiologies.

BACKGROUND: Pneumonia and diarrhea are leading causes of death for children under five (U5). It is challenging to estimate the total number of deaths and cause-specific mortality fractions. Two major efforts, one led by the Institute for Health Metrics and Evaluation (IHME) and the other led by the World Health Organization (WHO)/Child Health Epidemiology Reference Group (CHERG) created estimates for the burden of disease due to these two syndromes, yet their estimates differed greatly for 2010. METHODS: This paper discusses three main drivers of the differences: data sources, data processing, and covariates used for modelling. The paper discusses differences in the model assumptions for etiology-specific estimates and presents recommendations for improving future models. RESULTS: IHME's Global Burden of Disease (GBD) 2010 study estimated 6.8 million U5 deaths compared to 7.6 million U5 deaths from CHERG. The proportional differences between the pneumonia and diarrhea burden estimates from the two groups are much larger; GBD 2010 estimated 0.847 million and CHERG estimated 1.396 million due to pneumonia. Compared to CHERG, GBD 2010 used broader inclusion criteria for verbal autopsy and vital registration data. GBD 2010 and CHERG used different data processing procedures and therefore attributed the causes of neonatal death differently. The major difference in pneumonia etiologies modeling approach was the inclusion of observational study data; GBD 2010 included observational studies. CHERG relied on vaccine efficacy studies. DISCUSSION: Greater transparency in modeling methods and more timely access to data sources are needed. In October 2013, the Bill & Melinda Gates Foundation (BMGF) hosted an expert meeting to examine possible approaches for better estimation. The group recommended examining the impact of data by systematically excluding sources in their models. GBD 2.0 will use a counterfactual approach for estimating mortality from pathogens due to specific etiologies to overcome bias of the methods used in GBD 2010 going forward.

Oxygen tension modifies the 'stemness' of human cord blood-derived stem cells.

BACKGROUND AIMS: Amongst different stem cell populations derived from human cord blood (CB), unrestricted somatic stem cells (USSC) are distinguished from CB mesenchymal stromal cells (CB MSC) by expression patterns of homeobox (HOX) genes, delta-like1 homolog (DLK1) expression and adipogenic differentiation potential. In this study we investigated the effects of oxygen tension on the generation, proliferation and expression of stem cell marker genes, which could be critical during large-scale cell culture for clinical applications. METHODS: We cultured CB-derived stem cells at 5% and 20% O(2). Telomere length shortening was analyzed and we investigated gene expression using reverse-transcription (RT)-polymerase chain reaction (PCR) and real-time PCR. Additionally we performed adipogenic and osteogenic in vitro differentiation. Results. Altering the cultivation conditions of USSC or CB MSC from 20% to 5% O(2) had no significant impact. In contrast, cell populations derived from primary cultures prepared at 5% O(2) qualified as neither USSC nor as CB MSC. When converted to 20%, their proliferation was diminished, telomere shortening was accelerated, and two of six cell lines ceased expression of HOX genes. The HOX code of the other cell populations was not been affected by culture conditions. CONCLUSIONS: Altering culture conditions during generation can impact cell characteristics such as the HOX code. These effects need to be considered when dealing with cell cultures for clinical applications.

A Short Functional Neuroimaging Assay Using Attachment Scenes to Recruit Neural Correlates of Social Cognition-A Replication Study.

Attachment theory provides a conceptual framework to understand the impact of early child-caregiver experiences, such as loss or separation, on adult functioning and psychopathology. In the current study, scenes from the Adult Attachment Projective Picture System (AAP), a validated, commonly used standardized diagnostic instrument to assess adult attachment representations, were used to develop a short fMRI assay eliciting the neural correlates of encoding of potentially hurtful and threatening social situations such as social losses, rejections or loneliness. Data from healthy participants (N = 19) showed activations in brain areas associated with social cognition and semantic knowledge during exposure to attachment-related scenes compared to control scenes. Extensive activation of the temporal poles was observed, suggesting the use of semantic knowledge for generating social concepts and scripts. This knowledge may underlie our ability to explain and predict social interactions, a specific aspect of theory of mind or mentalization. In this replication study, we verified the effectiveness of a modified fMRI assay to assess the external validity of a previously used imaging paradigm to investigate the processing of emotionally negatively valenced and painful social interactions. Our data confirm the recruitment of brain areas associated with social cognition with our very short neuroimaging assay.

Genetic polymorphism of CYP2C19 and subcortical variability in the human adult brain.

Pharmacogenetic studies have shown involvement of cytochrome P450 enzymes in the metabolism of psychotropic drugs. However, expression and activity on endogenous substrates in the brain may underlie a constitutive role of these enzymes beyond drug metabolism. CYP2C19, which is expressed in the human fetal brain during neurodevelopment, shows affinity for endogenous compounds including monoaminergic neurotransmitters, steroid hormones, and endocannabinoids. In this study (N = 608), we looked at the genetic polymorphism of CYP2C19 and its potential associations with structural phenotypes of subcortical brain volume with structural imaging. Using two independent volume estimation techniques, we found converging evidence for a positive association between CYP2C19 activity scores, as inferred from the genotype, and basal ganglia and hippocampal volume. This association was present only in female individuals, raising the possibility that effects on brain morphology may arise through a mechanism involving the metabolism of estrogen steroids.

Effects of genetic variability of CYP2D6 on neural substrates of sustained attention during on-task activity.

The polymorphic drug-metabolizing enzyme CYP2D6, which is responsible for the metabolism of most psychoactive compounds, is expressed not only in the liver, but also in the brain. The effects of its marked genetic polymorphism on the individual capacity to metabolize drugs are well known, but its role in metabolism of neural substrates affecting behavior personality or cognition, suggested by its CNS expression, is a long-standing unresolved issue. To verify earlier findings suggesting a potential effect on attentional processes, we collected functional imaging data, while N = 415 participants performed a simple task in which the reward for correct responses varied. CYP2D6 allelic variants predicting higher levels of enzymatic activity level were positively associated with cortical activity in occipito-parietal areas as well as in a right lateralized network known to be activated by spatial attentional tasks. Reward-related modulation of activity in cortical areas was more pronounced in poor metabolizers. In conjunction with effects on reaction times, our findings provide evidence for reduced cognitive efficiency in rapid metabolizers compared to poor metabolizers in on-task attentional processes manifested through differential recruitment of a specific neural substrate.

Signals of anticipation of reward and of mean reward rates in the human brain.

Theoretical models of dopamine function stemming from reinforcement learning theory have emphasized the importance of prediction errors, which signal changes in the expectation of impending rewards. Much less is known about the effects of mean reward rates, which may be of motivational significance due to their role in computing the optimal effort put into exploiting reward opportunities. Here, we used a reinforcement learning model to design three functional neuroimaging studies and disentangle the effects of changes in reward expectations and mean reward rates, showing recruitment of specific regions in the brainstem regardless of prediction errors. While changes in reward expectations activated ventral striatal areas as in previous studies, mean reward rates preferentially modulated the substantia nigra/ventral tegmental area, deep layers of the superior colliculi, and a posterior pontomesencephalic region. These brainstem structures may work together to set motivation and attentional efforts levels according to perceived reward opportunities.

Mirror neuron activations in encoding of psychic pain in borderline personality disorder.

Borderline personality disorder (BPD) is characterized by pronounced emotional instability in interpersonal relations. Previous studies have shown increased activity in the amygdala, an imaging phenotype of negative affect. However, clinical accounts of BPD have drawn attention to deficits in social cognition and their likely role in engendering emotional instability. BPD patients show enhanced sensitivity to other people's emotions, while being less proficient in reading motives and reasons. In the present functional imaging study, we exposed BPD participants to stylized scenes of individuals affected by loss or separation, an issue to which these patients are particularly sensitive. Previously shown to activate the mirror neuron system, these mourning scenes were here also used to assess differential amygdala activity in stimuli of negative valence, but low arousal. Relative to controls, BPD patients were found to activate sensorimotor areas, a part of the mirror neuron system thought to encode basic aspects of the perception of motoric activity and pain. This contrasted with the activity of areas related to more complex aspects of social cognition, such as the inferior frontal gyrus. The amygdala was more active in patients when viewing these scenes, but this effect also showed a strong association with levels of depressiveness and neuroticism. After adjusting for these covariates, differences in amygdala activation were no longer significant. These findings are consistent with models of social cognition in BPD that attribute emotional sensitivity to emotional contagion through the mirror neuron system, in contrast to areas associated with more sophisticated forms of social cognition. These effects were accompanied by increased amygdala reactivity, consistently with the common occurrence of affective symptoms in these patients.

Repeated fMRI in measuring the activation of the amygdala without habituation when viewing faces displaying negative emotions.

Functional imaging studies of affective disorders have demonstrated abnormal activity in the amygdala in response to emotionally salient stimuli. Since in other studies this response has been shown to habituate during the scanning session, it is not clear if it may be of use in monitoring disease progression or remission, or in monitoring the effects of therapy, as habituation may confound normalisation of response. We investigated here amygdala activation in healthy participants exposed to displays of emotional facial expressions in a sample of N = 31 individuals assessed twice in an interval of three weeks. At this interval no habituation could be detected, suggesting the validity of this imaging assay in repeated assessments of amygdalar reactivity. However, the fusiform gyrus and the inferior frontal lobes showed decreases in activations that may be related to the role of these areas in encoding visual and emotional aspects of the stimuli.

A Computerized Version of the Scrambled Sentences Test.

The scrambled sentences test (SST), an experimental procedure that involves participants writing down their cognitions, has been used to elicit individual differences in depressiveness and vulnerability to depression. We describe here a modification of the SST to adapt it to computerized administration, with a particular view of its use in large samples and functional neuroimaging applications. In a first study with the computerized version, we reproduce the preponderance of positive cognitions in the healthy and the inverse association of these cognitions with individual measures of depressiveness. We also report a tendency of self-referential cognitions to elicit higher positive cognition rates. In a second study, we describe the patterns of neural activations elicited by emotional and neutral sentences in a functional neuroimaging study, showing that it replicates and extends previous findings obtained with the original version of the SST. During the formation of emotional cognitions, ventral areas such as the ventral anterior cingulus and the supramarginal gyrus were relatively activated. This activation pattern speaks for the recruitment of mechanisms coordinating motivational and associative processes in the formation of value-based decisions.

The iconography of mourning and its neural correlates: a functional neuroimaging study.

The present functional neuroimaging study focuses on the iconography of mourning. A culture-specific pattern of body postures of mourning individuals, mostly suggesting withdrawal, emerged from a survey of visual material. When used in different combinations in stylized drawings in our neuroimaging study, this material activated cortical areas commonly seen in studies of social cognition (temporo-parietal junction, superior temporal gyrus, and inferior temporal lobe), empathy for pain (somatosensory cortex), and loss (precuneus, middle/posterior cingular gyrus). This pattern of activation developed over time. While in the early phases of exposure lower association areas, such as the extrastriate body area, were active, in the late phases activation in parietal and temporal association areas and the prefrontal cortex was more prominent. These findings are consistent with the conventional and contextual character of iconographic material, and further differentiate it from emotionally negatively valenced and high-arousing stimuli. In future studies, this neuroimaging assay may be useful in characterizing interpretive appraisal of material of negative emotional valence.

Cost-effectiveness of a European ST-segment elevation myocardial infarction network: results from the Catalan Codi Infart network.

OBJECTIVES: To evaluate the cost-effectiveness of the ST-segment elevation myocardial infarction (STEMI) network of Catalonia (Codi Infart). DESIGN: Cost-utility analysis. SETTING: The analysis was from the Catalonian Autonomous Community in Spain, with a population of about 7.5 million people. PARTICIPANTS: Patients with STEMI treated within the autonomous community of Catalonia (Spain) included in the IAM CAT II-IV and Codi Infart registries. OUTCOME MEASURES: Costs included hospitalisation, procedures and additional personnel and were obtained according to the reperfusion strategy. Clinical outcomes were defined as 30-day avoided mortality and quality-adjusted life-years (QALYs), before (N=356) and after network implementation (N=2140). RESULTS: A substitution effect and a technology effect were observed; aggregate costs increased by 2.6%. The substitution effect resulted from increased use of primary coronary angioplasty, a relatively expensive procedure and a decrease in fibrinolysis. Primary coronary angioplasty increased from 31% to 89% with the network, and fibrinolysis decreased from 37% to 3%. Rescue coronary angioplasty declined from 11% to 4%, and no reperfusion from 21% to 4%. The technological effect was related to improvements in the percutaneous coronary intervention procedure that increased efficiency, reducing the average length of the hospital stay. Mean costs per patient decreased from €8306 to €7874 for patients with primary coronary angioplasty. Clinical outcomes in patients treated with primary coronary angioplasty did not change significantly, although 30-day mortality decreased from 7.5% to 5.6%. The incremental cost-effectiveness ratio resulted in an extra cost of €4355 per life saved (30-day mortality) and €495 per QALY. Below a cost threshold of €30,000, results were sensitive to variations in costs and outcomes. CONCLUSIONS: The Catalan STEMI network (Codi Infart) is cost-efficient. Further studies are needed in geopolitical different scenarios.

A novel culture device for the evaluation of three-dimensional extracellular matrix materials.

Cell-matrix interactions in a three-dimensional (3D) extracellular matrix (ECM) are of fundamental importance in living tissue, and their in vitro reconstruction in bioartificial structures represents a core target of contemporary tissue engineering concepts. For a detailed analysis of cell-matrix interaction under highly controlled conditions, we developed a novel ECM evaluation culture device (EECD) that allows for a precisely defined surface-seeding of 3D ECM scaffolds, irrespective of their natural geometry. The effectiveness of EECD was evaluated in the context of heart valve tissue engineering. Detergent decellularized pulmonary cusps were mounted in EECD and seeded with endothelial cells (ECs) to study EC adhesion, morphology and function on a 3D ECM after 3, 24, 48 and 96 h. Standard EC monolayers served as controls. Exclusive top-surface-seeding of 3D ECM by viable ECs was demonstrated by laser scanning microscopy (LSM), resulting in a confluent re-endothelialization of the ECM after 96 h. Cell viability and protein expression, as demonstrated by MTS assay and western blot analysis (endothelial nitric oxide synthase, von Willebrand factor), were preserved at maintained levels over time. In conclusion, EECD proves as a highly effective system for a controlled repopulation and in vitro analysis of cell-ECM interactions in 3D ECM.

Comparing the gene expression profile of stromal cells from human cord blood and bone marrow: lack of the typical "bone" signature in cord blood cells.

With regard to the bone-regenerative capacity, bone marrow stromal cells (BMSC) can still be termed the "gold standard." Nevertheless, neonatal stromal cells from cord blood (CB) feature advantages concerning availability, immaturity, and proliferation potential. The detailed gene expression analysis and overexpression of genes expressed differentially provide insight into the inherent capacity of stromal cells. Microarray and qRT-PCR analyses revealed closely related gene expression patterns of two stromal cell populations derived from CB. In contrast to the CB-derived cell types, BMSC displayed high expression levels of BSP, OSX, BMP4, OC, and PITX2. Lentiviral overexpression of BSP but not of OSX in CB-cells increased the capacity to form a mineralized matrix. BMP4 induced the secretion of proteoglycans during chondrogenic pellet culture and extended the osteogenic but reduced the adipogenic differentiation potential. BMSC revealed the typical osteogenic gene expression signature. In contrast, the CB-derived cell types exhibited a more immature gene expression profile and no predisposition towards skeletal development. The absence of BSP and BMP4-which were defined as potential key players affecting the differentiation potential-in neonatal stromal cells should be taken into consideration when choosing a cell source for tissue regeneration approaches.

Neonatal mesenchymal-like cells adapt to surrounding cells.

Hematopoietic cord blood (CB) transplantations are performed to treat patients with life-threatening diseases. Besides endothelial cells, the neonatal multipotent stromal cell subpopulations CDSCs (CB-derived stromal cells) and USSCs (unrestricted somatic stromal cells) are like bone marrow (BM) SCs interesting candidates for clinical applications if detailed knowledge is available. Clonal USSC compared to CDSC and BMSC lines differ in their developmental origin reflected by a distinct HOX expression. About 20 (out of 39) HOX genes are expressed in CDSCs (HOX+), whereas native USSCs reveal no HOX gene expression (HOX-). Moreover, USSCs display a lineage-specific absence of the adipogenic differentiation potential. As the specific HOX code can be ascribed to topographic bodysites it may be important to match the HOX code of transplanted cells to the tissue of interest. Herein co-culture experiments were performed, presenting a novel approach to modulate the differentiation potency of USSCs towards HOX positive stromal cells. After co-culturing native USSCs with CDSCs and BMSCs, USSCs adapt a positive HOX code and gain the adipogenic differentiation capacity. These results present for the first time modulation of a lineage-specific differentiation potential by co-culture. Finally, USSCs can be claimed as potential candidates to substitute unique progenitor cell populations in clinical approaches.

Distinct differentiation potential of "MSC" derived from cord blood and umbilical cord: are cord-derived cells true mesenchymal stromal cells?

Mesenchymal stromal cells (MSC) with distinct differentiation properties have been reported in many adult [eg, bone marrow (BM)] or fetal tissues [eg, cord blood (CB); umbilical cord (UC)] and are defined by their specific surface antigen expression and multipotent differentiation potential. The MSC identity of these cells should be validated by applying well-defined readout systems if a clinical application is considered. In order to determine whether cells isolated from human UC fulfill the criteria defined for MSC, the immunophenotype and differentiation potential including gene expression analysis of the most relevant lineage-specific markers were analyzed in the presented report in combination with the HOX-gene expression. Cells from the UC do not differentiate into osteoblasts demonstrated by Alizarin Red and Von Kossa staining in addition to real-time polymerase chain reaction (PCR)-analysis of runt-related transcription factor 2, bone sialoprotein, osteocalcin, osterix, bone morphogenetic proteins 2 and 4. Oil Red O staining as well as PCR analysis of peroxisome proliferator-activated receptor-gamma, fatty acid-binding protein 4, and perilipin revealed an absent adipogenic differentiation. The lack of potential to differentiate into chondrocytes was documented by Alcian-Blue periodic acid-Schiff, Safranin O staining, and real-time PCR analysis of SOX9. Furthermore, neither endothelial nor myogenic differentiation was documented after induction of UC-MSC. In comparison to CB- and BM-derived cells, UC cells revealed an absent trilineage differentiation capacity in vitro. Therefore, these cells should not be termed "mesenchymal stromal cells". The UC cells can be distinguished from CB- and BM-derived cells as well as from pericytes and foreskin fibroblasts by the expression of HOX-genes and the cell surface antigens CD56 and CD146.

The HOX Code as a "biological fingerprint" to distinguish functionally distinct stem cell populations derived from cord blood.

Mesenchymal stem cells (MSC) have been isolated from almost every adult tissue. In cord blood (CB), different non-hematopoietic CD45-, CD34- adherent cell populations can be generated: the cord blood derived MSC (CB-MSC), that behave almost like MSC from bone marrow (BM-MSC), and unrestricted somatic stem cells (USSC) which show a distinct differentiation potential into all three germ layers. However, distinguishing these populations easily by molecular markers is still a concern. In this study we were able to present the HOX expression pattern of USSC, CB-MSC and BM-MSC, which in fact allows a discrimination of these populations. Briefly, RT-PCR analysis of the HOX code revealed a high similarity between BM-MSC and CB-MSC, which are both HOX-positive, whereas USSC resembled H9 embryonic stem cells HOX-negative.Especially HOXA9, HOXB7, HOXC10 and HOXD8 are good candidate markers to discriminate MSC from USSC. Thus, our data suggest that the "biological fingerprint" based on the HOX code can be used to distinguish functionally distinct MSC populations derived from bone marrow and cord blood.

The Ni-mediated cyclocarbonylation of allyl halides and alkynes made catalytic. Evidence supporting the involvement of pseudoradical Ni(i) species in the mechanism.

We report here on a highly efficient catalytic method to synthesize intermolecularly the cyclopentane skeleton from starting products as simple as allyl halides, alkynes, and carbon monoxide under very mild reaction conditions by means of a substoichiometric amount of iron, acetone, and a catalytic amount of Ni(II) iodide.