References of "Luxen, André"
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See detailSynthesis and evaluation of boronic acids as inhibitors of Penicillin Binding Proteins of classes A, B and C.
Zervosen, Astrid ULg; Bouillez, André ULg; Herman, Alexandre et al

in Bioorganic & Medicinal Chemistry (2012), 20(12), 3915-24

In response to the widespread use of beta-lactam antibiotics bacteria have evolved drug resistance mechanisms that include the production of resistant Penicillin Binding Proteins (PBPs). Boronic acids are ... [more ▼]

In response to the widespread use of beta-lactam antibiotics bacteria have evolved drug resistance mechanisms that include the production of resistant Penicillin Binding Proteins (PBPs). Boronic acids are potent beta-lactamase inhibitors and have been shown to display some specificity for soluble transpeptidases and PBPs, but their potential as inhibitors of the latter enzymes is yet to be widely explored. Recently, a (2,6-dimethoxybenzamido)methylboronic acid was identified as being a potent inhibitor of Actinomadura sp. R39 transpeptidase (IC(50): 1.3muM). In this work, we synthesized and studied the potential of a number of acylaminomethylboronic acids as inhibitors of PBPs from different classes. Several derivatives inhibited PBPs of classes A, B and C from penicillin sensitive strains. The (2-nitrobenzamido)methylboronic acid was identified as a good inhibitor of a class A PBP (PBP1b from Streptococcus pneumoniae, IC(50)=26muM), a class B PBP (PBP2xR6 from Streptococcus pneumoniae, IC(50)=138muM) and a class C PBP (R39 from Actinomadura sp., IC(50)=0.6muM). This work opens new avenues towards the development of molecules that inhibit PBPs, and eventually display bactericidal effects, on distinct bacterial species. [less ▲]

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See detailA peptidoglycan fragment triggers beta-lactam resistance in Bacillus licheniformis.
Amoroso, Ana Maria ULg; Boudet, Julien; Berzigotti, Stephanie et al

in PLoS Pathogens (2012), 8(3), 1002571

To resist to beta-lactam antibiotics Eubacteria either constitutively synthesize a beta-lactamase or a low affinity penicillin-binding protein target, or induce its synthesis in response to the presence ... [more ▼]

To resist to beta-lactam antibiotics Eubacteria either constitutively synthesize a beta-lactamase or a low affinity penicillin-binding protein target, or induce its synthesis in response to the presence of antibiotic outside the cell. In Bacillus licheniformis and Staphylococcus aureus, a membrane-bound penicillin receptor (BlaR/MecR) detects the presence of beta-lactam and launches a cytoplasmic signal leading to the inactivation of BlaI/MecI repressor, and the synthesis of a beta-lactamase or a low affinity target. We identified a dipeptide, resulting from the peptidoglycan turnover and present in bacterial cytoplasm, which is able to directly bind to the BlaI/MecI repressor and to destabilize the BlaI/MecI-DNA complex. We propose a general model, in which the acylation of BlaR/MecR receptor and the cellular stress induced by the antibiotic, are both necessary to generate a cell wall-derived coactivator responsible for the expression of an inducible beta-lactam-resistance factor. The new model proposed confirms and emphasizes the role of peptidoglycan degradation fragments in bacterial cell regulation. [less ▲]

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See detailStealth macromolecular platforms for the design of MRI blood pool contrast agents
Grogna, Mathurin ULg; Cloots, Rudi ULg; Luxen, André ULg et al

in Polymer Chemistry (2011), 2(10), 2316-2327

Stealth macromolecular platforms bearing alkyne groups and poly(ethylene oxide) brushes were synthesized by reversible addition fragmentation chain transfer (RAFT) polymerization. The anchoring of Gd3 ... [more ▼]

Stealth macromolecular platforms bearing alkyne groups and poly(ethylene oxide) brushes were synthesized by reversible addition fragmentation chain transfer (RAFT) polymerization. The anchoring of Gd3+-chelates bearing an azide group was then carried out by the Huisgen 1,3-dipolar cycloaddition (“click”) reaction in mild conditions, leading to macrocontrast agents for MRI applications. The gadolinium complex is hidden in the PEO shell that renders the macrocontrast agents free of any cytotoxicity and stealth to proteins of the immune system. Relaxometry measurements have evidenced an improved relaxivity of the macrocontrast agent compared to ungrafted gadolinium chelate. Moreover, this relaxivity is further enhanced when the spacer length between the Gd3+-chelate and the polymer backbone is shorter, as the result of its decreased tumbling rate. These novel products are therefore promising candidates for MRI applications. [less ▲]

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See detailConvenient grafting through approach for the preparation of stealth polymeric blood pool magnetic resonance imaging contrast agents
Grogna, Mathurin ULg; Cloots, Rudi ULg; Luxen, André ULg et al

in Journal of Polymer Science. Part A, Polymer Chemistry (2011), 49(17), 3700-3708

New hydrosoluble magnetic resonance imaging (MRI) macrocontrast agents are synthesized by reversible addition fragmentation chain transfer (RAFT) copolymerization of poly(ethylene oxide) methyl ether ... [more ▼]

New hydrosoluble magnetic resonance imaging (MRI) macrocontrast agents are synthesized by reversible addition fragmentation chain transfer (RAFT) copolymerization of poly(ethylene oxide) methyl ether acrylate (PEOMA) with an acrylamide bearing a ligand for gadolinium, followed by the complexation of Gd3+. This convenient and simple grafting through approach leads to macrocontrast agents with a high relaxivity at high frequency that is imparted by the restricted tumbling of the Gd3+ complex caused by its attachment to the polymer backbone. Importantly a very low protein adsorption is also evidenced by the hemolytic CH50 test. It is the result of the poly(ethylene oxide) (PEO) brush that efficiently hides the gadolinium complex and renders it stealth to the proteins of the immune system. Improved contrast and long blood circulating properties are thus expected for these macrocontrast agents. [less ▲]

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See detailAutomated synthesis of [18F] FBEM for labeling of thiol containing compounds
Paris, Jérôme ULg; Thonon, David ULg; Kaisin, Geoffroy ULg et al

Poster (2011, September 01)

[18F]FBEM, i.e. N-[2-(4-[18F]fluorobenzamido)ethyl]maleimide, is a useful synthon employed for the specific radiolabeling of thiol containing compounds, including peptides and proteins. The aim of the ... [more ▼]

[18F]FBEM, i.e. N-[2-(4-[18F]fluorobenzamido)ethyl]maleimide, is a useful synthon employed for the specific radiolabeling of thiol containing compounds, including peptides and proteins. The aim of the present work was to develop a fast, reproducible and fully automated synthesis of this compound in order to improve its availabilty as well as for obvious radioprotection matters. [less ▲]

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See detailHypnotic modulation of resting state fMRI default mode and extrinsic network connectivity
Demertzi, Athina ULg; Soddu, Andrea ULg; FAYMONVILLE, Marie-Elisabeth ULg et al

in Progress in Brain Research (2011), 193

Resting state fMRI (functional magnetic resonance imaging) acquisitions are characterized by low-frequency spontaneous activity in a default mode network (encompassing medial brain areas and linked to ... [more ▼]

Resting state fMRI (functional magnetic resonance imaging) acquisitions are characterized by low-frequency spontaneous activity in a default mode network (encompassing medial brain areas and linked to self-related processes) and an anticorrelated “extrinsic” system (encompassing lateral frontoparietal areas and modulated via external sensory stimulation). In order to better determine the functional contribution of these networks to conscious awareness, we here sought to transiently modulate their relationship by means of hypnosis. We used independent component analysis (ICA) on resting state fMRI acquisitions during normal wakefulness, under hypnotic state, and during a control condition of autobiographical mental imagery. As compared to mental imagery, hypnosis-induced modulation of resting state fMRI networks resulted in a reduced “extrinsic” lateral frontoparietal cortical connectivity, possibly reflecting a decreased sensory awareness. The default mode network showed an increased connectivity in bilateral angular and middle frontal gyri, whereas its posterior midline and parahippocampal structures decreased their connectivity during hypnosis, supposedly related to an altered “self” awareness and posthypnotic amnesia. In our view, fMRI resting state studies of physiological (e.g., sleep or hypnosis), pharmacological (e.g., sedation or anesthesia), and pathological modulation (e.g., coma or related states) of “intrinsic” default mode and anticorrelated “extrinsic” sensory networks, and their interaction with other cerebral networks, will further improve our understanding of the neural correlates of subjective awareness. [less ▲]

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See detailPerformance evaluation of the General Electric eXplore CT 120 micro-CT using the vmCT phantom.
Bahri, Mohamed Ali ULg; Warnock, Geoffrey ULg; Plenevaux, Alain ULg et al

in Nuclear Instruments & Methods in Physics Research Section A (2011), 648

The eXplore CT 120 is the latest generation micro-CT from General Electric. It is equipped with a high power tube and a flat panel detector. It allows high resolution and high contrast fast CT scanning of ... [more ▼]

The eXplore CT 120 is the latest generation micro-CT from General Electric. It is equipped with a high power tube and a flat panel detector. It allows high resolution and high contrast fast CT scanning of small animals. The aim of this study was to compare the performance of the eXplore CT 120 with the one of the eXplore Ultra, its predecessor for which the methodology using the vmCT phantom was already described [1]. The phantom was imaged using typical rat (fast scan or F) or mouse (in vivo bone scan or H) scanning protocols. With the slanted edge method, a 10% modulation transfer function (MTF) was observed at 4.4 (F) and 3.9-4.4 (H) mm-1 corresponding to 114 μm resolution. A fairly larger MTF was obtained with the coil method with the MTF for the thinnest coil (3.3 mm-1 ) equal to 0.32 (F) and 0.34 (H). The geometric accuracy was better than 0.3%. There was a highly linear (R2 > 0.999) relationship between measured and expected CT numbers for both the CT number accuracy and linearity sections of the phantom. A cupping effect was clearly seen on the uniform slices and the uniformity-to-noise ratio ranged from 0.52 (F) to 0.89 (H). The air CT number depended on the amount of polycarbonate surrounding the area where it was measured: a difference as high as approximately 200 HU was observed. This hindered the calibration of this scanner in HU. This is likely due to the absence of corrections for beam hardening and scatter in the reconstruction software. However in view of the high linearity of the system, the implementation of these corrections would allow a good quality calibration of the scanner in HU. In conclusion, the eXplore CT 120 achieved a better spatial resolution than the eXplore Ultra (based on previously reported specifications) and future software developments to include beam hardening and scatter corrections will make the new generation CT scanner even more promising. [less ▲]

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See detailUse of a beta microprobe system to measure arterial input function in PET via an arteriovenous shunt in rats
Warnock, Geoffrey ULg; Bahri, Mohamed Ali ULg; Goblet, David ULg et al

in European Journal of Nuclear Medicine and Molecular Imaging Research (2011), 1

Kinetic modeling of physiological function using imaging techniques requires the accurate measurement of the time-activity curve of the tracer in plasma, known as the arterial input function (IF). The ... [more ▼]

Kinetic modeling of physiological function using imaging techniques requires the accurate measurement of the time-activity curve of the tracer in plasma, known as the arterial input function (IF). The measurement of IF can be achieved through manual blood sampling, the use of small counting systems such as beta microprobes, or by derivation from PET images. Previous studies using beta microprobe systems to continuously measure IF have suffered from high background counts. In the present study, a light-insensitive beta microprobe with a temporal resolution of up to 1 s was used in combination with a pump-driven femoral arteriovenous shunt to measure IF in rats. The shunt apparatus was designed such that the placement of the beta microprobe was highly reproducible. The probe-derived IF was compared to that obtained from manual sampling at 5-s intervals and IF derived from a left ventricle VOI in a dynamic PET image of the heart. Probe-derived IFs were very well matched to that obtained by "gold standard" manual blood sampling, but with an increased temporal resolution of up to 1 s. The area under the curve (AUC) ratio between probe- and manually derived IFs was 1.07 ± 0.05 with a coefficient of variation of 0.04. However, image-derived IFs were significantly underestimated compared to the manually sampled IFs, with an AUC ratio of 0.76 ± 0.24 with a coefficient of variation of 0.32. IF derived from the beta microprobe accurately represented the IF as measured by blood sampling, was reproducible, and was more accurate than an image-derived technique. The use of the shunt removed problems of tissue-background activity, and the use of a light-tight probe with minimal gamma sensitivity refined the system. The probe/shunt apparatus can be used in both microprobe and PET studies. [less ▲]

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See detailDesign and synthesis of novel DOTA(Gd3+)–polymer conjugates as potential MRI contrast agents
Grogna, Mathurin ULg; Cloots, Rudi ULg; Luxen, André ULg et al

in Journal of Materials Chemistry (2011), 21(34), 12917-12926

Conventional low molecular weight gadolinium based Magnetic Resonance Imaging (MRI) contrast agents such as Magnevist® are very useful for imaging tissues. However, at the high magnetic fields used in ... [more ▼]

Conventional low molecular weight gadolinium based Magnetic Resonance Imaging (MRI) contrast agents such as Magnevist® are very useful for imaging tissues. However, at the high magnetic fields used in modern MRI equipments, their relaxivity (contrasting efficiency) is rather poor. The grafting of the gadolinium complex onto macromolecules is a way to enhance their relaxivity provided that the rotational motion of the complex is decreased significantly. Here we report the design of novel Gd3+ based MRI contrast agents with improved relaxivity and potential long blood circulation life-time. We investigate the grafting of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, 1,4,7-tris(1,1-dimethylethyl) ester (DO3AtBu-NH2; a precursor of Gd3+ ligand) onto well-defined functional copolymers bearing activated esters (succinimidyl esters) and poly(ethylene oxide) (PEO) chains required for stealthiness. The tert-butyl groups of grafted DO3AtBu-NH2 are then deprotected by trifluoroacetic acid followed by complexation of Gd3+. Addition of free DOTA at the end of the reaction is necessary to leave the pure and stable water soluble macrocontrast agent. Importantly it shows a relaxivity at high frequencies that is 300% higher than that of the ungrafted gadolinium complex. These novel functional copolymers are therefore promising candidates as macromolecular contrast agents for MRI applications. [less ▲]

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See detailUnexpected tricovalent binding mode of boronic acids within the active site of a penicillin binding protein.
Zervosen, Astrid ULg; Herman, Raphaël ULg; Kerff, Frédéric ULg et al

in Journal of the American Chemical Society (2011)

Boronic acids bearing appropriate side chains are good inhibitors of serine amidohydrolases. The boron usually adopts a tetrahedral conformation, bound to the nucleophilic serine of the active site and ... [more ▼]

Boronic acids bearing appropriate side chains are good inhibitors of serine amidohydrolases. The boron usually adopts a tetrahedral conformation, bound to the nucleophilic serine of the active site and mimicking the transition state of the enzymatic reaction. We have solved the structures of complexes of a penicillin-binding protein, the DD-peptidase from Actinomadura sp. R39, with four amidomethylboronic acids (2,6 dimethoxybenzamidomethylboronic acid, phenylacetamidomethylboronic acid, 2-chlorobenzamidomethylboronic acid, and 2-nitrobenzamidomethylboronic acid) and the pinacol ester derived from phenylacetamidomethylboronic acid. We found that, in each case, the boron forms a tricovalent adduct with Ogamma of Ser49, Ser298, and the terminal amine group of Lys410, three key residues involved in the catalytic mechanism of penicillin-binding proteins. This represents the first tricovalent enzyme-inhibitor adducts observed by crystallography. In two of the five R39-boronate structures, the boronic acid is found as a tricovalent adduct in two monomers of the asymmetric unit and as a monocovalent adduct with the active serine in the two remaining monomers of the asymmetric unit. Formation of the tricovalent complex from a classical monocovalent complex may involve rotation around the Ser49 Calpha-Cbeta bond to place the boron in a position to interact with Ser298 and Lys410, and a twisting of the side chain amide such that its carbonyl oxygen is able to hydrogen bond to the oxyanion hole NH of Thr413. Biphasic kinetics were observed in three of the five cases and details of the reaction between R39 and 2,6-dimethoxybenzamidomethylboronic acid were studied. Observation of biphasic kinetics was not, however, thought to be correlated to formation of tricovalent complexes, assuming that the latter do form in solution. Based on the crystallographic and kinetic results, a reaction scheme for this unexpected inhibition by boronic acids is proposed. [less ▲]

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See detail[18F]fallypride binding in the mouse brain: test-retest and effects of registration
Bahri, Mohamed Ali ULg; Geuzaine, Annabelle ULg; Warnock, Geoffrey ULg et al

Conference (2011, January 17)

The quantification of in vivo receptor kinetics with PET tracer experiments is an intricate and challenging problem especially for small animals such as rats and mice. A test-retest scan is usually set up ... [more ▼]

The quantification of in vivo receptor kinetics with PET tracer experiments is an intricate and challenging problem especially for small animals such as rats and mice. A test-retest scan is usually set up in order to confirm an observed experimental effect or to examine the reliability of the experiment design. Inadequate processing of the image data may also mask small effects. The purpose of this study was to investigate the effect of image registration on [18F]fallypride binding potentials calculated from PET mouse test-retest data. Sub-optimal registration affected the quantification of in vivo receptor kinetics with [18F]fallypride. The absence of anatomical information in the [18F]fallypride image and the lack of a homogeneous tracer distribution, even during the earlier minutes of the scan, lead to erroneous automatic registration. A FDG scan after each [18F]fallypride test could improve registration as FDG provides a more homogeneous brain image. Variability in the data could also result from stress induced by anaesthesia or the experimental environment. [less ▲]

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See detailImage Quality evaluation for 124I in the microPET Focus 120 scanner using the NEMA NU4-2008 phantom
Bahri, Mohamed Ali ULg; Warnock, Geoffrey ULg; Taleb, Dounia ULg et al

Conference (2011, January 17)

Physical properties of iodine-124 such as its high positron energy, corresponding large positron range in tissue and the fraction of the single γ-photons emitted may have detrimental effects on the PET ... [more ▼]

Physical properties of iodine-124 such as its high positron energy, corresponding large positron range in tissue and the fraction of the single γ-photons emitted may have detrimental effects on the PET image quality. The purpose of this work was to evaluate the image quality for iodine-124 in the small animal microPET Focus 120 scanner using the NEMA NU4-2008 image quality phantom. Although the 2 ns timing window gives higher recovery coefficients and slightly lower spill-over ratios and combined with the 350-590 keV energy window gives the lowest spill-over ratio, the combination of the 350-650 keV and 6 ns windows seems to be the best compromise to obtain images with high contrast and low noise content. [less ▲]

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See detailSleep contributes to the strengthening of some memories over others, depending on hippocampal activity at learning.
Rauchs, Géraldine; Feyers, Dorothée ULg; Landeau, Brigitte et al

in Journal of Neuroscience (2011), 31(7), 2563-2568

Memory consolidation benefits from sleep. Besides strengthening some memory traces, another crucial, albeit overlooked, function of memory is also to erase irrelevant information. Directed forgetting is ... [more ▼]

Memory consolidation benefits from sleep. Besides strengthening some memory traces, another crucial, albeit overlooked, function of memory is also to erase irrelevant information. Directed forgetting is an experimental approach consisting in presenting “to be remembered” and “to be forgotten” information, that allows selectively decreasing or increasing the strength of individual memory traces according to the instruction provided at learning. This paradigm was used in combination with fMRI to determine, in Humans, what specifically triggers at encoding sleep-dependent compared to time-dependent consolidation. Our data indicate that relevant items which subjects strived to memorize are consolidated during sleep to a greater extend than items that participants did not intend to learn. This process appears to depend on a differential activation of the hippocampus at encoding, which acts as a signal for the offline reprocessing of relevant memories during post-learning sleep episodes. [less ▲]

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See detail"Relevance vector machine" consciousness classifier applied to cerebral metabolism of vegetative and locked-in patients.
Phillips, Christophe ULg; Bruno, Marie-Aurélie ULg; Maquet, Pierre ULg et al

in NeuroImage (2011), 56(2), 797808

The vegetative state is a devastating condition where patients awaken from their coma (i.e., open their eyes) but fail to show any behavioural sign of conscious awareness. Locked-in syndrome patients also ... [more ▼]

The vegetative state is a devastating condition where patients awaken from their coma (i.e., open their eyes) but fail to show any behavioural sign of conscious awareness. Locked-in syndrome patients also awaken from their coma and are unable to show any motor response to command (except for small eye movements or blinks) but recover full conscious awareness of self and environment. Bedside evaluation of residual cognitive function in coma survivors often is difficult because motor responses may be very limited or inconsistent. We here aimed to disentangle vegetative from "locked-in" patients by an automatic procedure based on machine learning using fluorodeoxyglucose PET data obtained in 37 healthy controls and in 13 patients in a vegetative state. Next, the trained machine was tested on brain scans obtained in 8 patients with locked-in syndrome. We used a sparse probabilistic Bayesian learning framework called "relevance vector machine" (RVM) to classify the scans. The trained RVM classifier, applied on an input scan, returns a probability value (p-value) of being in one class or the other, here being "conscious" or not. Training on the control and vegetative state groups was assessed with a leave-one-out cross-validation procedure, leading to 100% classification accuracy. When applied on the locked-in patients, all scans were classified as "conscious" with a mean p-value of .95 (min .85). In conclusion, even with this relatively limited data set, we could train a classifier distinguishing between normal consciousness (i.e., wakeful conscious awareness) and the vegetative state (i.e., wakeful unawareness). Cross-validation also indicated that the clinical classification and the one predicted by the automatic RVM classifier were in accordance. Moreover, when applied on a third group of "locked-in" consciously aware patients, they all had a strong probability of being similar to the normal controls, as expected. Therefore, RVM classification of cerebral metabolic images obtained in coma survivors could become a useful tool for the automated PET-based diagnosis of altered states of consciousness. [less ▲]

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See detailStructure Guided Development of Potent Reversibly Binding Penicillin Binding Protein Inhibitors
Woon, Esther C. Y.; Zervosen, Astrid ULg; Sauvage, Eric ULg et al

in ACS Medicinal Chemistry letters (2011), 2 (3)

Following from the evaluation of different types of electrophiles, combined modeling and crystallographic analyses are used to generate potent boronic acid based inhibitors of a penicillin binding protein ... [more ▼]

Following from the evaluation of different types of electrophiles, combined modeling and crystallographic analyses are used to generate potent boronic acid based inhibitors of a penicillin binding protein. The results suggest that a structurally informed approach to penicillin binding protein inhibition will be useful for the development of both improved reversibly binding inhibitors, including boronic acids, and acylating inhibitors, such as β-lactams. [less ▲]

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See detailTwo distinct neuronal networks mediate the awareness of environment and of self
Vanhaudenhuyse, Audrey ULg; Demertzi, Athina ULg; Schabus, Manuel et al

in Journal of Cognitive Neuroscience (2011), 23(3), 570-578

Evidence from functional neuroimaging studies on resting state suggests that there are two distinct anticorrelated cortical systems that mediate conscious awareness: an "extrinsic" system that encompasses ... [more ▼]

Evidence from functional neuroimaging studies on resting state suggests that there are two distinct anticorrelated cortical systems that mediate conscious awareness: an "extrinsic" system that encompasses lateral fronto-parietal areas and has been linked with processes of external input (external awareness), and an "intrinsic" system which encompasses mainly medial brain areas and has been associated with internal processes (internal awareness). The aim of our study was to explore the neural correlates of resting state by providing behavioral and neuroimaging data from healthy volunteers. With no a priori assumptions, we first determined behaviorally the relationship between external and internal awareness in 31 subjects. We found a significant anticorrelation between external and internal awareness with a mean switching frequency of 0.05 Hz (range: 0.01-0.1 Hz). Interestingly, this frequency is similar to BOLD fMRI slow oscillations. We then evaluated 22 healthy volunteers in an fMRI paradigm looking for brain areas where BOLD activity correlated with "internal" and "external" scores. Activation of precuneus/posterior cingulate, anterior cingulate/mesiofrontal cortices, and parahippocampal areas ("intrinsic system") was linearly linked to intensity of internal awareness, whereas activation of lateral fronto-parietal cortices ("extrinsic system") was linearly associated with intensity of external awareness. [less ▲]

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See detailSynthesis and hydrolytic stability of novel 3-[18F]fluoroethoxybis(1-methylethyl)silyl]propanaminebased prosthetic groups
collet, Charlotte; Lamandé-Langle, Sandrine; Balentova, Eva et al

Poster (2011)

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