Background Neuroimaging studies of emotion in schizophrenia have reported abnormalities in amygdala and other regions, although divergent results and heterogeneous paradigms complicate conclusions ...from single experiments. To identify more consistent patterns of dysfunction, a meta-analysis of functional imaging studies of emotion was undertaken. Methods Searching Medline and PsycINFO databases through January 2011, 88 potential articles were identified, of which 26 met inclusion criteria, comprising 450 patients with schizophrenia and 422 healthy comparison subjects. Contrasts were selected to include emotion perception and emotion experience. Foci from individual studies were subjected to a voxelwise meta-analysis using multilevel kernel density analysis. Results For emotional experience, comparison subjects showed greater activation in the left occipital pole. For emotional perception, schizophrenia subjects showed reduced activation in bilateral amygdala, visual processing areas, anterior cingulate cortex, dorsolateral frontal cortex, medial frontal cortex, and subcortical structures. Schizophrenia subjects showed greater activation in the cuneus, parietal lobule, precentral gyrus, and superior temporal gyrus. Combining across studies and eliminating studies that did not balance on effort and stimulus complexity eliminated most differences in visual processing regions as well as most areas where schizophrenia subjects showed a greater signal. Reduced reactivity of the amygdala appeared primarily in implicit studies of emotion, whereas deficits in anterior cingulate cortex activity appeared throughout all contrasts. Conclusions Processing emotional stimuli, schizophrenia patients show reduced activation in areas engaged by emotional stimuli, although in some conditions, schizophrenia patients exhibit increased activation in areas outside those traditionally associated with emotion, possibly representing compensatory processing.
Time-lapse electrical resistivity tomography (ERT) measurements provide indirectobservations of hydrological processes in the Earth's shallow subsurface at high spatial and temporal resolution. ERT ...has been used in the past decades to detect leaks and monitor the evolution of associated contaminant plumes. Specifically, inverted resistivity images allow visualization of the dynamic changes in the structure of the plume. However, existing methods do not allow the direct estimation of leak parameters (e.g. leak rate, location, etc.) and their uncertainties. We propose an ensemble-based data assimilation framework that evaluates proposed hydrological models against observed time-lapse ERT measurements without directly inverting for the resistivities. Each proposed hydrological model is run through the parallel coupled hydro-geophysical simulation code PFLOTRAN-E4D to obtain simulated ERT measurements. The ensemble of model proposals is then updated using an iterative ensemble smoother. We demonstrate the proposed framework on synthetic and field ERT data from controlled tracer injection experiments. Our results show that the approach allows joint identification of contaminant source location, initial release time, and solute loading from the cross-borehole time-lapse ERT data, alongside with an assessment of uncertainties in these estimates. We demonstrate a reduction in site-wide uncertainty by comparing the prior and posterior plume mass discharges at a selected image plane. This framework is particularly attractive to sites that have previously undergone extensive geological investigation (e.g., nuclear sites). It is well suited to complement ERT imaging and we discuss practical issues in its application to field problems.
Estimation of leak parameters and their uncertainties using raw geophysical data and data assimilation. Display omitted
•A new data assimilation framework is proposed to estimate leak parameters directly from ERT data given prior site models.•Our results show reductions in uncertainties of both leak parameters and site-wide solute mass discharge.•This framework is particularly attractive to sites that have undergone extensive site investigation previously.
Phosphorylation of proteins on tyrosine (Tyr) residues evolved in metazoan organisms as a mechanism of coordinating tissue growth
. Multicellular eukaryotes typically have more than 50 distinct ...protein Tyr kinases that catalyse the phosphorylation of thousands of Tyr residues throughout the proteome
. How a given Tyr kinase can phosphorylate a specific subset of proteins at unique Tyr sites is only partially understood
. Here we used combinatorial peptide arrays to profile the substrate sequence specificity of all human Tyr kinases. Globally, the Tyr kinases demonstrate considerable diversity in optimal patterns of residues surrounding the site of phosphorylation, revealing the functional organization of the human Tyr kinome by substrate motif preference. Using this information, Tyr kinases that are most compatible with phosphorylating any Tyr site can be identified. Analysis of mass spectrometry phosphoproteomic datasets using this compendium of kinase specificities accurately identifies specific Tyr kinases that are dysregulated in cells after stimulation with growth factors, treatment with anti-cancer drugs or expression of oncogenic variants. Furthermore, the topology of known Tyr signalling networks naturally emerged from a comparison of the sequence specificities of the Tyr kinases and the SH2 phosphotyrosine (pTyr)-binding domains. Finally we show that the intrinsic substrate specificity of Tyr kinases has remained fundamentally unchanged from worms to humans, suggesting that the fidelity between Tyr kinases and their protein substrate sequences has been maintained across hundreds of millions of years of evolution.
•Social dysfunction in bipolar disorder (BD) may be due to altered mentalizing.•Individuals with BD showed reduced activation in the mentalizing brain system.•Aberrant activity of the mentalizing ...system was associated with poorer cognition/social cognition.
Bipolar disorder (BD) is associated with a range of social cognitive deficits. This study investigated the functioning of the mentalizing brain system in BD probed by an eye gaze perception task during fMRI. Compared with healthy controls (n = 21), BD participants (n = 14) showed reduced preferential activation for self-directed gaze discrimination in the medial prefrontal cortex (mPFC) and temporo-parietal junction (TPJ), which was associated with poorer cognition/social cognition. Aberrant functions of the mentalizing system should be further investigated as marker of social dysfunction and treatment targets.
Abstract
Background
Deficits in social cognition are pervasive in schizophrenia (SZ) and strong predictors of poor functional outcomes. Understanding of the mechanisms underlying critical social ...cognitive dysfunctions in SZ will advance our understanding of the disorder and help design targeted treatment. In this presentation, we examine a basic building block of social cognition—eye gaze perception—in SZ and bipolar psychosis (BP). Given the frequent documentations of visual perceptual anomaly in SZ, we specifically evaluate the role of visual disturbances in altered gaze processing in psychosis. We used psychophysics to isolate distinctive cognitive processes involved in gaze perception (Study 1) and applied dynamic causal modeling (DCM) to fMRI data to illuminate aberrant brain dynamics responsible for altered gaze processing (Study 2).
Methods
In Study 1, 157 participants (47 SZ; 55 BP; and 55 healthy controls, HC) viewed faces with varying gaze directions and made two-forced choice eye contact judgments (“yes” or “no”). In each individual, eye contact endorsement was examined as a logistic function of gaze direction. The slope and absolute threshold of this perception curve were used to index, respectively, visual perceptual sensitivity and self-referential bias. Individual measures and group differences were estimated using hierarchical Bayesian modeling. Markov Chain Monte Carlo (MCMC) implemented in WinBUGS was used to sample from the joint posterior distribution to estimate posterior probabilities of the parameters. In Study 2, 27 SZ participants and 22 HC completed a gaze perception task during BOLD fMRI. They viewed faces with varying gaze directions and made two-forced choice judgments of eye contact or gender (control task). Time series from the V2 visual cortex (V2), posterior superior temporal sulcus (pSTS), inferior parietal lobule (IPL), and posterior medial prefrontal cortex (pMPFC) were extracted and subject to DCM analysis. Initial model family comparison showed that models with gaze modulations on both bottom-up connections from V2 and top-down connections from pMFC had the highest evidence compared with models with gaze modulations on either bottom-up or top-down connections. Models from this model family were then subject to post-hoc Bayesian model selection to select the best model for each individual. Parameter estimates of the winning model were taken to group-level analyses using t-tests.
Results
In Study 1, both clinical groups showed high posterior probabilities of reduced perceptual sensitivity (SZ: 99.96%; BP: 98.7%) and increased self-referential bias (SZ: 98.7%; BP: 93.71%) when compared with HC during gaze perception. Although BP generally positioned in between SZ and HC, it was not statistically distinguishable from SZ. In Study 2, DCM revealed that, as expected, attending to gaze (vs. gender) strengthened bottom-up connections from V2 to IPL (t= 3.50, p = .001) and to pSTS (t= 2.53, p = .015) across participants. Compared with HC, SZ showed weakened sensory input to V2 (t = -2.12, p = .042) and reduced feedforward connectivity from V2 to IPL (t = -2.09, p = .045). When processing gaze (vs. gender), HC relaxed pMFC suppression of V2, perhaps to allow more data-driven processes; conversely, SZ increased pMFC inhibition of V2 (t = -3.22, p = .002), presumably to compensate for impaired bottom-up processes by relying more on higher-level cognition to determine the self-referential nature of gaze.
Conclusions
These findings suggest that gaze perception in psychosis, regardless of diagnostic category, is characterized by altered cognitive processes at both the perceptual and interpretation levels. However, effective connectivity analyses suggest that abnormal gaze processing may originate from dysfunctions of the visual cortex, and that aberrant top-down processes may be a compensatory mechanism. We are currently working on replicating these fMRI findings and will be launching an experimental study using transcranial magnetic stimulation to confirm the causal role of visual cortical dysfunction in altered gaze processing in psychosis.
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