Vossel S.,University College London |
Vossel S.,Jülich Research Center |
Mathys C.,University College London |
Mathys C.,ETH Zurich |
And 4 more authors.
Journal of Neuroscience | Year: 2015
The deployment of visuospatial attention and the programming of saccades are governed by the inferred likelihood of events. In the present study, we combined computational modeling of psychophysical data with fMRI to characterize the computational and neural mechanisms underlying this flexible attentional control. Sixteen healthy human subjects performed a modified version of Posner’s location-cueing paradigm in which the percentage of cue validity varied in time and the targets required saccadic responses. Trialwise estimates of the certainty (precision) of the prediction that the target would appear at the cued location were derived from a hierarchical Bayesian model fitted to individual trialwise saccadic response speeds. Trial-specific model parameters then entered analyses of fMRI data as parametric regressors. Moreover, dynamic causal modeling (DCM) was performed to identify the most likely functional architecture of the attentional reorienting network and its modulation by (Bayes-optimal) precision-dependent attention. While the frontal eye fields (FEFs), intraparietal sulcus, and temporoparietal junction (TPJ) of both hemispheres showed higher activity on invalid relative to valid trials, reorienting responses in right FEF, TPJ, and the putamen were significantly modulated by precision-dependent attention. Our DCM results suggested that the precision of predictability underlies the attentional modulation of the coupling of TPJ with FEF and the putamen. Our results shed new light on the computational architecture and neuronal network dynamics underlying the contextsensitive deployment of visuospatial attention. © 2015 the authors.
Stephan K.E.,ETH Zurich |
Stephan K.E.,University College London |
Stephan K.E.,Max Planck Institute for Metabolism Research |
Iglesias S.,ETH Zurich |
And 2 more authors.
Neuron | Year: 2015
Functional neuroimaging has made fundamental contributions to our understanding of brain function. It remains challenging, however, to translate these advances into diagnostic tools for psychiatry. Promising new avenues for translation are provided by computational modeling of neuroimaging data. This article reviews contemporary frameworks for computational neuroimaging, with a focus on forward models linking unobservable brain states to measurements. These approaches-biophysical network models, generative models, and model-based fMRI analyses of neuromodulation-strive to move beyond statistical characterizations and toward mechanistic explanations of neuroimaging data. Focusing on schizophrenia as a paradigmatic spectrum disease, we review applications of these models to psychiatric questions, identify methodological challenges, and highlight trends of convergence among computational neuroimaging approaches. We conclude by outlining a translational neuromodeling strategy, highlighting the importance of openly available datasets from prospective patient studies for evaluating the clinical utility of computational models. Psychiatry lacks diagnostic tools that enable clinical predictions and treatment selection for individual patients. Computational models of neuroimaging data offer a promising new avenue. Focusing on schizophrenia, this article reviews clinical applications, methodological challenges, and future developments of computational neuroimaging. © 2015 Elsevier Inc.
Wensveen F.M.,University of Rijeka |
Jelencic V.,University of Rijeka |
Valentic S.,University of Rijeka |
Sestan M.,University of Rijeka |
And 9 more authors.
Nature Immunology | Year: 2015
An important cause of obesity-induced insulin resistance is chronic systemic inflammation originating in visceral adipose tissue (VAT). VAT inflammation is associated with the accumulation of proinflammatory macrophages in adipose tissue, but the immunological signals that trigger their accumulation remain unknown. We found that a phenotypically distinct population of tissue-resident natural killer (NK) cells represented a crucial link between obesity-induced adipose stress and VAT inflammation. Obesity drove the upregulation of ligands of the NK cell-activating receptor NCR1 on adipocytes; this stimulated NK cell proliferation and interferon-γ (IFN-γ) production, which in turn triggered the differentiation of proinflammatory macrophages and promoted insulin resistance. Deficiency of NK cells, NCR1 or IFN-γ prevented the accumulation of proinflammatory macrophages in VAT and greatly ameliorated insulin sensitivity. Thus NK cells are key regulators of macrophage polarization and insulin resistance in response to obesity-induced adipocyte stress. © 2015 Nature America, Inc. All rights reserved.
Turpin S.M.,Max Planck Institute for Metabolism Research |
Nicholls H.T.,Max Planck Institute for Metabolism Research |
Willmes D.M.,Max Planck Institute for Metabolism Research |
Mourier A.,CECAD |
And 16 more authors.
Cell Metabolism | Year: 2014
Ceramides increase during obesity and promote insulin resistance. Ceramides vary in acyl-chain lengths from C14:0 to C30:0 and are synthesized by six ceramide synthase enzymes (CerS1-6). It remains unresolved whether obesity-associated alterations of specific CerSs and their defined acyl-chain length ceramides contribute to the manifestation of metabolic diseases. Here we reveal that CERS6 mRNA expression and C16:0 ceramides are elevated in adipose tissue of obese humans, and increased CERS6 expression correlates with insulin resistance. Conversely, CerS6-deficient (CerS6Δ/Δ) mice exhibit reduced C16:0 ceramides and are protected from high-fat-diet-induced obesity and glucose intolerance. CerS6 deletion increases energy expenditure and improves glucose tolerance, not only in CerS6Δ/Δ mice, but also in brown adipose tissue- (CerS6ΔBAT) and liver-specific (CerS6ΔLIVER) CerS6 knockout mice. CerS6 deficiency increases lipid utilization in BAT and liver. These experiments highlight CerS6 inhibition as a specific approach for the treatment of obesity and type 2 diabetes mellitus, circumventing the side effects of global ceramide synthesis inhibition. © 2014 Elsevier Inc.
Morgan M.,City University London |
Morgan M.,Max Planck Institute for Metabolism Research
Current Biology | Year: 2015
A new experiment shows that the perceived motion path of a textured object is affected both by the path of the object and by the motion of texture within it, but that eye movements attempting to intercept the object are unaffected by the texture movement. © 2015 Elsevier Ltd All rights reserved.
Nguyen P.-H.,University of Cologne |
Fedorchenko O.,University of Cologne |
Rosen N.,University of Cologne |
Koch M.,University of Cologne |
And 6 more authors.
Cancer Cell | Year: 2016
Survival of chronic lymphocytic leukemia (CLL) cells strictly depends on the support of an appropriate tumor microenvironment. Here, we demonstrate that LYN kinase is essential for CLL progression. Lyn deficiency results in a significantly reduced CLL burden in vivo. Loss of Lyn within leukemic cells reduces B cell receptor (BCR) signaling including BTK phosphorylation, but surprisingly does not affect leukemic cell expansion. Instead, syngeneic CLL transplantation of CLL cells into Lyn- or Btk-deficient recipients results in a strongly delayed leukemic progression and prolonged survival. Moreover, Lyn deficiency in macrophages hinders nursing functions for CLL cells, which is mediated by direct contact rather than secretion of soluble factors. Taken together, LYN and BTK seem essential for the formation of a microenvironment supporting leukemic growth. © 2016 Elsevier Inc.
Steculorum S.M.,Max Planck Institute for Metabolism Research |
Steculorum S.M.,University of Cologne |
Bruning J.C.,Max Planck Institute for Metabolism Research |
Bruning J.C.,University of Cologne
Cell Metabolism | Year: 2016
The ventromedial nucleus of the hypothalamus (VMH) is a central region known to maintain glucose homeostasis. Toda et al. (2016) unravel a new mechanism underlying VMH-dependent regulation of systemic glucose homeostasis via uncoupling protein 2 (UCP2)-mediated control of mitochondrial dynamics and activation of glucose-excited neurons. © 2016 Elsevier Inc.
Mauer J.,Max Planck Institute for Metabolism Research |
Denson J.L.,Max Planck Institute for Metabolism Research |
Bruning J.C.,Max Planck Institute for Metabolism Research
Trends in Immunology | Year: 2015
Owing to its abundance in inflammatory settings, interleukin IL-6 is frequently viewed as a proinflammatory cytokine, with functions that parallel those of tumor necrosis factor (TNF) and IL-1β in the context of inflammation. However, accumulating evidence points to a broader role for IL-6 in a variety of (patho)physiological conditions, including functions related to the resolution of inflammation. We review recent findings on the complex biological functions governed by IL-6 signaling, focusing on its role in inflammation-associated cancer and metabolic disorders such as obesity and type 2 diabetes mellitus (T2DM). We propose that the anti-inflammatory functions of IL-6 may extend to multiple settings and cell types, and suggest that these dimensions should be incorporated in therapeutic approaches to these diseases. Finally, we outline important areas of inquiry towards understanding this pleiotropic cytokine. © 2015.
Heiss W.-D.,Max Planck Institute for Metabolism Research
Cerebrovascular Diseases | Year: 2016
Background: Malignant middle cerebral artery infarction is a devastating condition, with up to 80% mortality in conservatively treated patients. The pathophysiology of this stroke is characterized by a large core of severe ischemia and only a relatively small rim of penumbra. Due to the fast development of irreversible morphological damage, cytotoxic edema occurs immediately in a large portion of the ischemic territory. The subsequent damage of the tight junctions leads to the breakdown of the blood brain barrier and vasogenic brain edema, resulting in space-occupying brain swelling. The progressive vasogenic edema reaches its maximum after 1 to several days and exerts a mechanical force on surrounding tissue structures leading to midline shift and transtentorial herniation and finally brain stem compression and death. Summary: Early severe neurological symptoms - hemiparesis, gaze deviation, higher cortical signs - followed by headache, vomiting, papillo edema and reduced consciousness may predict the deleterious course. Imaging supports the suspected diagnosis with hypodense changes on CT extending beyond 50% of the MCA territory. The size of the probably infarcted tissue and a midline shift on CT as well as the size of the lesion on diffusion-weighted MRI are predictive of a malignant course. Reduction of cerebral blood flow below a critical value and volume of irreversible tissue damage detected by positron emission tomography in the early hours after the stroke are indicative of progression to malignant infarction with increased intracranial pressure (ICP) and decreased tissue oxygen tension observed by multimodal neuromonitoring in the later course. Treatment options of malignant infarction include general measures to limit the extent of space-occupying edema, but these therapies have not been efficacious. Only surgical intervention with decompressive hemicraniectomy (DHC) was successful in relieving the effects of increased ICP and of the deleterious shifts of brain tissue. Several controlled clinical trials have proven the efficacy of DHC with a significant decrease in mortality and improved functional outcome. However, DHC must be performed early and with a large diameter, regardless of the age of patients, but in patients beyond 60 years, the higher likelihood of resulting severe disability should be taken into consideration. Key Messages: Malignant MCA infarction can be predicted early with a high sensitivity by neuroimaging. The early diagnosis is mandatory for DHC, which was shown to reduce mortality and improve functional outcome in several controlled clinical trials. © 2015 S. Karger AG, Basel.
Hoehn M.,Max Planck Institute for Metabolism Research
Georgian medical news | Year: 2015
The investigation of dynamic processes with long time profiles can profit from longitudinal noninvasive imaging modalities. In this contribution the potential and limits of in vivo imaging modalities are discussed as regards monitoring neuro-inflammation. Complementary information derived from magnetic resonance imaging (MRI), positron emission tomography (PET) and bioluminescence imaging (BLI) will be presented.