Neural activity of the anterior insula in emotional processing depends on the individuals' emotional susceptibility

Differences in personality factors between individuals may manifest themselves with different patterns of neural activity while individuals process stimuli with emotional content. We attempted to verify this hypothesis by investigating emotional susceptibility (ES), a specific emotional trait of the human personality defined as the tendency to "experience feelings of discomfort, helplessness, inadequacy and vulnerability" after exposure to stimuli with emotional valence. By administering a questionnaire evaluating the individuals' ES, we selected two groups of participants with high and low ES respectively. Then, we used functional magnetic resonance imaging to investigate differences between the groups in the neural activity involved while they were processing emotional stimuli in an explicit (focusing on the content of the stimuli) or an incidental (focusing on spatial features of the stimuli, irrespectively of their content) way. The results showed a selective difference in brain activity between groups only in the explicit processing of the emotional stimuli: bilateral activity of the anterior insula was present in subjects with high ES but not in subjects with low ES. This difference in neural activity within the anterior insula proved to be purely functional since no brain morphological differences were found between groups, as assessed by a voxel-based morphometry analysis. Although the role of the anterior insula in the processing of contexts perceived as emotionally salient is well established, the present study provides the first evidence of a modulation of the insular activity depending on the individuals' ES trait of personality.

Activity in inferior parietal and medial prefrontal cortex signals the accumulation of evidence in a probability learning task.

In an uncertain environment, probabilities are key to predicting future events and making adaptive choices. However, little is known about how humans learn such probabilities and where and how they are encoded in the brain, especially when they concern more than two outcomes. During functional magnetic resonance imaging (fMRI), young adults learned the probabilities of uncertain stimuli through repetitive sampling. Stimuli represented payoffs and participants had to predict their occurrence to maximize their earnings. Choices indicated loss and risk aversion but unbiased estimation of probabilities. BOLD response in medial prefrontal cortex and angular gyri increased linearly with the probability of the currently observed stimulus, untainted by its value. Connectivity analyses during rest and task revealed that these regions belonged to the default mode network. The activation of past outcomes in memory is evoked as a possible mechanism to explain the engagement of the default mode network in probability learning. A BOLD response relating to value was detected only at decision time, mainly in striatum. It is concluded that activity in inferior parietal and medial prefrontal cortex reflects the amount of evidence accumulated in favor of competing and uncertain outcomes.

Detection of neuronal activity and metabolism in a model of dehydration-induced anorexia in rats at 14.1 T using manganese-enhanced MRI and 1H MRS.

In this study, hypothalamic activation was performed by dehydration-induced anorexia (DIA) and overnight food suppression (OFS) in female rats. The assessment of the hypothalamic response to these challenges by manganese-enhanced MRI showed increased neuronal activity in the paraventricular nuclei (PVN) and lateral hypothalamus (LH), both known to be areas involved in the regulation of food intake. The effects of DIA and OFS were compared by generating T-score maps. Increased neuronal activation was detected in the PVN and LH of DIA rats relative to OFS rats. In addition, the neurochemical profile of the PVN and LH were measured by (1) H MRS at 14.1T. Significant increases in metabolite levels were measured in DIA and OFS relative to control rats. Statistically significant increases in γ-aminobutyric acid were found in DIA (p=0.0007) and OFS (p<0.001) relative to control rats. Lactate increased significantly in DIA (p=0.03), but not in OFS, rats. This work shows that manganese-enhanced MRI coupled to (1) H MRS at high field is a promising noninvasive method for the investigation of the neural pathways and mechanisms involved in the control of food intake, in the autonomic and endocrine control of energy metabolism and in the regulation of body weight.

In vivo enzymatic activity of acetylCoA synthetase in skeletal muscle revealed by 13C turnover from hyperpolarized [1-13C]acetate to [1-13C]acetylcarnitine

BACKGROUND: Acetate metabolism in skeletal muscle is regulated by acetylCoA synthetase (ACS). The main function of ACS is to provide cells with acetylCoA, a key molecule for numerous metabolic pathways including fatty acid and cholesterol synthesis and the Krebs cycle. METHODS: Hyperpolarized [1-(13)C]acetate prepared via dissolution dynamic nuclear polarization was injected intravenously at different concentrations into rats. The (13)C magnetic resonance signals of [1-(13)C]acetate and [1-(13)C]acetylcarnitine were recorded in vivo for 1min. The kinetic rate constants related to the transformation of acetate into acetylcarnitine were deduced from the 3s time resolution measurements using two approaches, either mathematical modeling or relative metabolite ratios. RESULTS: Although separated by two biochemical transformations, a kinetic analysis of the (13)C label flow from [1-(13)C]acetate to [1-(13)C]acetylcarnitine led to a unique determination of the activity of ACS. The in vivo Michaelis constants for ACS were KM=0.35±0.13mM and Vmax=0.199±0.031μmol/g/min. CONCLUSIONS: The conversion rates from hyperpolarized acetate into acetylcarnitine were quantified in vivo and, although separated by two enzymatic reactions, these rates uniquely defined the activity of ACS. The conversion rates associated with ACS were obtained using two analytical approaches, both methods yielding similar results. GENERAL SIGNIFICANCE: This study demonstrates the feasibility of directly measuring ACS activity in vivo and, since the activity of ACS can be affected by various pathological states such as cancer or diabetes, the proposed method could be used to non-invasively probe metabolic signatures of ACS in diseased tissue.

Conjugation of genetically-engineered protein phosphatases to magnetic particles for okadaic acid detection

This work presents the functional characterisation of a protein phosphatase 2A (PP2A) catalytic subunit obtained by genetic engineering and its conjugation to magnetic particles (MPs) via metal coordination chemistry for the subsequent development of assays for diarrheic lipophilic marine toxins. Colorimetric assays with free enzyme have allowed the determination of the best enzyme activity stabiliser, which is glycerol at 10%. They have also demonstrated that the recombinant enzyme can be as sensitive towards okadaic acid (OA) (LOD=2.3μg/L) and dinophysistoxin-1 (DTX-1) (LOD=15.2μg/L) as a commercial PP2A and, moreover, it has a higher operational stability, which makes possible to perform the protein phosphatase inhibition assay (PPIA) with a lower enzyme amount. Once conjugated to MPs, the PP2A catalytic subunit still retains its enzyme activity and it can also be inhibited by OA (LOD=30.1μg/L).

IRM cardiaque: imagerie de référence dans le diagnostic de la myocardite aiguë [Cardiac magnetic resonance in acute myocarditis: a new non-invasive diagnostic gold standard?].

Acute myocarditis was until recently one of the most difficult diagnoses in cardiology. The spectrum of signs and symptoms is very wide, the usual non-invasive tests lack specificity and the myocardial biopsy is only performed in a minority of cases to confirm the diagnosis. Due to its unique ability to directly image myocardial necrosis, fibrosis and oedema, cardiac magnetic resonance (CMR) is now considered the primary tool for noninvasive assessment of patients with suspected myocarditis. CMR is also useful for monitoring disease activity under treatment. Myocarditis has been associated with the development of dilated cardiomyopathy; CMR could play a role in the follow-up of such cases to detect the progression toward a dilatative phenotype. Precise mapping of myocardial lesions with cardiac MRI is invaluable to guide myocardial biopsy and increase its diagnostic yield by improving sensitivity.

MP2RAGE Multiple Sclerosis Magnetic Resonance Imaging at 3 T.

OBJECTIVES: Lesion detection and characterization in multiple sclerosis (MS) are an essential part of its clinical diagnosis and an important research field. In this pilot study, we applied the recently introduced two inversion-contrast magnetization-prepared rapid gradient echo sequence (MP2RAGE) to patients with early-stage MS.¦MATERIALS AND METHODS: The MP2RAGE is a 3-dimensional (3D) magnetization-prepared rapid gradient echo derivative providing homogeneous T1 weighting and simultaneous T1 mapping. The MP2RAGE performance was compared with that of 2 clinical routine sequences (2D fluid-attenuated inversion recovery [FLAIR] and 3D magnetization-prepared rapid gradient echo [MP-RAGE]) and 2 state-of-the art clinical research sequences (the 3D FLAIR-SPACE [sampling perfection with application-optimized contrasts by using different flip-angle evolutions], a fluid-attenuated variable flip-angle fast spin echo technique, and the 3D double-inversion recovery SPACE). A cohort of 10 early-stage female MS patients (age, 31.6 ± 4.7 years; disease duration, 3.8 ± 1.9 years; median expanded disability status scale score, 1.75) and 10 age- and gender-matched controls were enrolled after approval of the local institutional review board was obtained. Multiple sclerosis lesions were identified and assigned to brain locations and tissue types by two experienced physicians in all 5 contrasts. Subsequently, lesions were manually delineated for comparison and statistical analysis of lesion count, volume and quantitative measures.¦RESULTS AND CONCLUSIONS: The results show that the 3D T1-weighted high-resolution MP2RAGE contrast provides a sensitive means for MS lesion assessment. The additional quantitative T1 relaxation time maps obtained with the MP2RAGE provide further potential diagnostic and prognostic information that could help (a) to better discriminate lesion subtypes and (b) to stage and predict the activity and the evolution of MS. Results also indicate that the T2-weighted double-inversion recovery and FLAIR-SPACE contrasts are attractive complements to the MP2RAGE for lesion detection.

Monitoring Disease Activity and Progression in Crohn's Disease. A Swiss Perspective on the IBD Ahead 'Optimised Monitoring' Recommendations.

BACKGROUND AND AIMS: The structured IBD Ahead 'Optimised Monitoring' programme was designed to obtain the opinion, insight and advice of gastroenterologists on optimising the monitoring of Crohn's disease activity in four settings: (1) assessment at diagnosis, (2) monitoring in symptomatic patients, (3) monitoring in asymptomatic patients, and (4) the postoperative follow-up. For each of these settings, four monitoring methods were discussed: (a) symptom assessment, (b) endoscopy, (c) laboratory markers, and (d) imaging. Based on literature search and expert opinion compiled during an international consensus meeting, recommendations were given to answer the question 'which diagnostic method, when, and how often'. The International IBD Ahead Expert Panel advised to tailor this guidance to the healthcare system and the special prerequisites of each country. The IBD Ahead Swiss National Steering Committee proposes best-practice recommendations adapted for Switzerland. METHODS: The IBD Ahead Steering Committee identified key questions and provided the Swiss Expert Panel with a structured literature research. The expert panel agreed on a set of statements. During an international expert meeting the consolidated outcome of the national meetings was merged into final statements agreed by the participating International and National Steering Committee members - the IBD Ahead 'Optimized Monitoring' Consensus. RESULTS: A systematic assessment of symptoms, endoscopy findings, and laboratory markers with special emphasis on faecal calprotectin is deemed necessary even in symptom-free patients. The choice of recommended imaging methods is adapted to the specific situation in Switzerland and highlights the importance of ultrasonography and magnetic resonance imaging besides endoscopy. CONCLUSION: The recommendations stress the importance of monitoring disease activity on a regular basis and by objective parameters, such as faecal calprotectin and endoscopy with detailed documentation of findings. Physicians should not rely on symptoms only and adapt the monitoring schedule and choice of options to individual situations. © 2014 S. Karger AG, Basel.

A pipeline approach with spatial information for segmenting multiple sclerosis lesions on brain magnetic resonance imaging

Background: Conventional magnetic resonance imaging (MRI) techniques are highly sensitive to detect multiple sclerosis (MS) plaques, enabling a quantitative assessment of inflammatory activity and lesion load. In quantitative analyses of focal lesions, manual or semi-automated segmentations have been widely used to compute the total number of lesions and the total lesion volume. These techniques, however, are both challenging and time-consuming, being also prone to intra-observer and inter-observer variability.Aim: To develop an automated approach to segment brain tissues and MS lesions from brain MRI images. The goal is to reduce the user interaction and to provide an objective tool that eliminates the inter- and intra-observer variability.Methods: Based on the recent methods developed by Souplet et al. and de Boer et al., we propose a novel pipeline which includes the following steps: bias correction, skull stripping, atlas registration, tissue classification, and lesion segmentation. After the initial pre-processing steps, a MRI scan is automatically segmented into 4 classes: white matter (WM), grey matter (GM), cerebrospinal fluid (CSF) and partial volume. An expectation maximisation method which fits a multivariate Gaussian mixture model to T1-w, T2-w and PD-w images is used for this purpose. Based on the obtained tissue masks and using the estimated GM mean and variance, we apply an intensity threshold to the FLAIR image, which provides the lesion segmentation. With the aim of improving this initial result, spatial information coming from the neighbouring tissue labels is used to refine the final lesion segmentation.Results:The experimental evaluation was performed using real data sets of 1.5T and the corresponding ground truth annotations provided by expert radiologists. The following values were obtained: 64% of true positive (TP) fraction, 80% of false positive (FP) fraction, and an average surface distance of 7.89 mm. The results of our approach were quantitatively compared to our implementations of the works of Souplet et al. and de Boer et al., obtaining higher TP and lower FP values.Conclusion: Promising MS lesion segmentation results have been obtained in terms of TP. However, the high number of FP which is still a well-known problem of all the automated MS lesion segmentation approaches has to be improved in order to use them for the standard clinical practice. Our future work will focus on tackling this issue.

Surface-functionalized ultrasmall superparamagnetic nanoparticles as magnetic delivery vectors for camptothecin.

Drug-nanoparticle conjugates: The anticancer drug camptothecin (CPT) was covalently linked at the surface of ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) via a linker, allowing drug release by cellular esterases. Nanoparticles were hierarchically built to achieve magnetically-enhanced drug delivery to human cancer cells and antiproliferative activity.The linking of therapeutic drugs to ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) allowing intracellular release of the active drug via cell-specific mechanisms would achieve tumor-selective magnetically-enhanced drug delivery. To validate this concept, we covalently attached the anticancer drug camptothecin (CPT) to biocompatible USPIOs (iron oxide core, 9-10 nm; hydrodynamic diameter, 52 nm) coated with polyvinylalcohol/polyvinylamine (PVA/aminoPVA). A bifunctional, end-differentiated dicarboxylic acid linker allowed the attachment of CPT to the aminoPVA as a biologically labile ester substrate for cellular esterases at one end, and as an amide at the other end. These CPT-USPIO conjugates exhibited antiproliferative activity in vitro against human melanoma cells. The intracellular localization of CPT-USPIOs was confirmed by transmission electron microscopy (iron oxide core), suggesting localization in lipid vesicles, and by fluorescence microscopy (CPT). An external static magnetic field applied during exposure increased melanoma cell uptake of the CPT-USPIOs.

Prognostic value of cortically induced motor evoked activity by TMS in chronic stroke: caveats from a very revealing single clinical case

Background: We report the case of a chronic stroke patient (62 months after injury) showing total absence of motor activity evoked by transcranial magnetic stimulation (TMS) of spared regions of the left motor cortex, but near-to-complete recovery of motor abilities in the affected hand. Case presentation: Multimodal investigations included detailed TMS based motor mapping, motor evoked potentials (MEP), and Cortical Silent period (CSP) as well as functional magnetic resonance imaging (fMRI) of motor activity, MRI based lesion analysis and Diffusion Tensor Imaging (DTI) Tractography of corticospinal tract (CST). Anatomical analysis revealed a left hemisphere subinsular lesion interrupting the descending left CST at the level of the internal capsule. The absence of MEPs after intense TMS pulses to the ipsilesional M1, and the reversible suppression of ongoing electromyographic (EMG) activity (indexed by CSP) demonstrate a weak modulation of subcortical systems by the ipsilesional left frontal cortex, but an inability to induce efficient descending volleys from those cortical locations to right hand and forearm muscles. Functional MRI recordings under grasping and finger tapping patterns involving the affected hand showed slight signs of subcortical recruitment, as compared to the unaffected hand and hemisphere, as well as the expected cortical activations. Conclusions: The potential sources of motor voluntary activity for the affected hand in absence of MEPs are discussed. We conclude that multimodal analysis may contribute to a more accurate prognosis of stroke patients.

Low-frequency transcranial magnetic stimulation over left dorsal premotor cortex improves the dynamic control of visuospatially cued actions.

Left rostral dorsal premotor cortex (rPMd) and supramarginal gyrus (SMG) have been implicated in the dynamic control of actions. In 12 right-handed healthy individuals, we applied 30 min of low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) over left rPMd to investigate the involvement of left rPMd and SMG in the rapid adjustment of actions guided by visuospatial cues. After rTMS, subjects underwent functional magnetic resonance imaging while making spatially congruent button presses with the right or left index finger in response to a left- or right-sided target. Subjects were asked to covertly prepare motor responses as indicated by a directional cue presented 1 s before the target. On 20% of trials, the cue was invalid, requiring subjects to readjust their motor plan according to the target location. Compared with sham rTMS, real rTMS increased the number of correct responses in invalidly cued trials. After real rTMS, task-related activity of the stimulated left rPMd showed increased task-related coupling with activity in ipsilateral SMG and the adjacent anterior intraparietal area (AIP). Individuals who showed a stronger increase in left-hemispheric premotor-parietal connectivity also made fewer errors on invalidly cued trials after rTMS. The results suggest that rTMS over left rPMd improved the ability to dynamically adjust visuospatial response mapping by strengthening left-hemispheric connectivity between rPMd and the SMG-AIP region. These results support the notion that left rPMd and SMG-AIP contribute toward dynamic control of actions and demonstrate that low-frequency rTMS can enhance functional coupling between task-relevant brain regions and improve some aspects of motor performance.

Computational modeling of resting-state activity demonstrates markers of normalcy in children with prenatal or perinatal stroke.

Children who sustain a prenatal or perinatal brain injury in the form of a stroke develop remarkably normal cognitive functions in certain areas, with a particular strength in language skills. A dominant explanation for this is that brain regions from the contralesional hemisphere "take over" their functions, whereas the damaged areas and other ipsilesional regions play much less of a role. However, it is difficult to tease apart whether changes in neural activity after early brain injury are due to damage caused by the lesion or by processes related to postinjury reorganization. We sought to differentiate between these two causes by investigating the functional connectivity (FC) of brain areas during the resting state in human children with early brain injury using a computational model. We simulated a large-scale network consisting of realistic models of local brain areas coupled through anatomical connectivity information of healthy and injured participants. We then compared the resulting simulated FC values of healthy and injured participants with the empirical ones. We found that the empirical connectivity values, especially of the damaged areas, correlated better with simulated values of a healthy brain than those of an injured brain. This result indicates that the structural damage caused by an early brain injury is unlikely to have an adverse and sustained impact on the functional connections, albeit during the resting state, of damaged areas. Therefore, these areas could continue to play a role in the development of near-normal function in certain domains such as language in these children.

Task-Driven Activity Reduces the Cortical Activity Space of the Brain: Experiment and Whole-Brain Modeling.

How a stimulus or a task alters the spontaneous dynamics of the brain remains a fundamental open question in neuroscience. One of the most robust hallmarks of task/stimulus-driven brain dynamics is the decrease of variability with respect to the spontaneous level, an effect seen across multiple experimental conditions and in brain signals observed at different spatiotemporal scales. Recently, it was observed that the trial-to-trial variability and temporal variance of functional magnetic resonance imaging (fMRI) signals decrease in the task-driven activity. Here we examined the dynamics of a large-scale model of the human cortex to provide a mechanistic understanding of these observations. The model allows computing the statistics of synaptic activity in the spontaneous condition and in putative tasks determined by external inputs to a given subset of brain regions. We demonstrated that external inputs decrease the variance, increase the covariances, and decrease the autocovariance of synaptic activity as a consequence of single node and large-scale network dynamics. Altogether, these changes in network statistics imply a reduction of entropy, meaning that the spontaneous synaptic activity outlines a larger multidimensional activity space than does the task-driven activity. We tested this model's prediction on fMRI signals from healthy humans acquired during rest and task conditions and found a significant decrease of entropy in the stimulus-driven activity. Altogether, our study proposes a mechanism for increasing the information capacity of brain networks by enlarging the volume of possible activity configurations at rest and reliably settling into a confined stimulus-driven state to allow better transmission of stimulus-related information.

Direct noninvasive estimation of myocardial tricarboxylic acid cycle flux in vivo using hyperpolarized (13)C magnetic resonance.

BACKGROUND: The heart relies on continuous energy production and imbalances herein impair cardiac function directly. The tricarboxylic acid (TCA) cycle is the primary means of energy generation in the healthy myocardium, but direct noninvasive quantification of metabolic fluxes is challenging due to the low concentration of most metabolites. Hyperpolarized (13)C magnetic resonance spectroscopy (MRS) provides the opportunity to measure cellular metabolism in real time in vivo. The aim of this work was to noninvasively measure myocardial TCA cycle flux (VTCA) in vivo within a single minute. METHODS AND RESULTS: Hyperpolarized [1-(13)C]acetate was administered at different concentrations in healthy rats. (13)C incorporation into [1-(13)C]acetylcarnitine and the TCA cycle intermediate [5-(13)C]citrate was dynamically detected in vivo with a time resolution of 3s. Different kinetic models were established and evaluated to determine the metabolic fluxes by simultaneously fitting the evolution of the (13)C labeling in acetate, acetylcarnitine, and citrate. VTCA was estimated to be 6.7±1.7μmol·g(-1)·min(-1) (dry weight), and was best estimated with a model using only the labeling in citrate and acetylcarnitine, independent of the precursor. The TCA cycle rate was not linear with the citrate-to-acetate metabolite ratio, and could thus not be quantified using a ratiometric approach. The (13)C signal evolution of citrate, i.e. citrate formation was independent of the amount of injected acetate, while the (13)C signal evolution of acetylcarnitine revealed a dose dependency with the injected acetate. The (13)C labeling of citrate did not correlate to that of acetylcarnitine, leading to the hypothesis that acetylcarnitine formation is not an indication of mitochondrial TCA cycle activity in the heart. CONCLUSIONS: Hyperpolarized [1-(13)C]acetate is a metabolic probe independent of pyruvate dehydrogenase (PDH) activity. It allows the direct estimation of VTCA in vivo, which was shown to be neither dependent on the administered acetate dose nor on the (13)C labeling of acetylcarnitine. Dynamic (13)C MRS coupled to the injection of hyperpolarized [1-(13)C]acetate can enable the measurement of metabolic changes during impaired heart function.