MR spectroscopy of the human brain with enhanced signal intensity at ultrashort echo times on a clinical platform at 3T and 7T.

Recently, the spin-echo full-intensity acquired localized (SPECIAL) spectroscopy technique was proposed to unite the advantages of short TEs on the order of milliseconds (ms) with full sensitivity and applied to in vivo rat brain. In the present study, SPECIAL was adapted and optimized for use on a clinical platform at 3T and 7T by combining interleaved water suppression (WS) and outer volume saturation (OVS), optimized sequence timing, and improved shimming using FASTMAP. High-quality single voxel spectra of human brain were acquired at TEs below or equal to 6 ms on a clinical 3T and 7T system for six volunteers. Narrow linewidths (6.6 +/- 0.6 Hz at 3T and 12.1 +/- 1.0 Hz at 7T for water) and the high signal-to-noise ratio (SNR) of the artifact-free spectra enabled the quantification of a neurochemical profile consisting of 18 metabolites with Cramér-Rao lower bounds (CRLBs) below 20% at both field strengths. The enhanced sensitivity and increased spectral resolution at 7T compared to 3T allowed a two-fold reduction in scan time, an increased precision of quantification for 12 metabolites, and the additional quantification of lactate with CRLB below 20%. Improved sensitivity at 7T was also demonstrated by a 1.7-fold increase in average SNR (= peak height/root mean square [RMS]-of-noise) per unit-time.

Brain-derived neurotrophic factor enhances the expression of the monocarboxylate transporter 2 through translational activation in mouse cultured cortical neurons.

MCT2 is the predominant neuronal monocarboxylate transporter allowing lactate use as an alternative energy substrate. It is suggested that MCT2 is upregulated to meet enhanced energy demands after modifications in synaptic transmission. Brain-derived neurotrophic factor (BDNF), a promoter of synaptic plasticity, significantly increased MCT2 protein expression in cultured cortical neurons (as shown by immunocytochemistry and western blot) through a translational regulation at the synaptic level. Brain-derived neurotrophic factor can cause translational activation through different signaling pathways. Western blot analyses showed that p44/p42 mitogen-activated protein kinase (MAPK), Akt, and S6 were strongly phosphorylated on BDNF treatment. To determine by which signal transduction pathway(s) BDNF mediates its upregulation of MCT2 protein expression, the effect of specific inhibitors for p38 MAPK, phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK), p44/p42 MAPK (ERK), and Janus kinase 2 (JAK2) was evaluated. It could be observed that the BDNF-induced increase in MCT2 protein expression was almost completely blocked by all inhibitors, except for JAK2. These data indicate that BDNF induces an increase in neuronal MCT2 protein expression by a mechanism involving a concomitant stimulation of PI3K/Akt/mTOR/S6, p38 MAPK, and p44/p42 MAPK. Moreover, our observations suggest that changes in MCT2 expression could participate in the process of synaptic plasticity induced by BDNF.

Dependence of brain intravoxel incoherent motion perfusion parameters on the cardiac cycle.

Measurement of microvascular perfusion with Intravoxel Incoherent Motion (IVIM) MRI is gaining interest. Yet, the physiological influences on the IVIM perfusion parameters ("pseudo-diffusion" coefficient D*, perfusion fraction f, and flow related parameter fD*) remain insufficiently characterized. In this article, we hypothesize that D* and fD*, which depend on blood speed, should vary during the cardiac cycle. We extended the IVIM model to include time dependence of D* = D*(t), and demonstrate in the healthy human brain that both parameters D* and fD* are significantly larger during systole than diastole, while the diffusion coefficient D and f do not vary significantly. The results non-invasively demonstrate the pulsatility of the brain's microvasculature.

Visual representation of food in the brain : effects of repeated exposure and gut hormone secretion

The thesis at hand is concerned with the spatio-temporal brain mechanisms of visual food perception as investigated by electrical neuroimaging. Due to the increasing prevalence of obesity and its associated challenges for public health care, there is a need to better understand behavioral and brain processes underlying food perception and food-based decision-making. The first study (Study A) of this thesis was concerned with the role of repeated exposure to visual food cues. In our everyday lives we constantly and repeatedly encounter food and these exposures influence our food choices and preferences. In Study A, we therefore applied electrical neuroimaging analyses of visual evoked potentials to investigate the spatio-temporal brain dynamics linked to the repeated viewing of high- and low-energy food cues (published manuscript: "The role of energetic value in dynamic brain response adaptation during repeated food image viewing" (Lietti et al., 2012)). In this study, we found that repetitions differentially affect behavioral and brain mechanisms when high-energy, as opposed to low-energy foods and non-food control objects, were viewed. The representation of high-energy food remained invariant between initial and repeated exposures indicating that the sight of high-energy dense food induces less behavioral and neural adaptation than the sight of low-energy food and non-food control objects. We discuss this finding in the context of the higher salience (due to greater motivation and higher reward or hedonic valuation) of energy- dense food that likely generates a more mnemonically stable representation. In turn, this more invariant representation of energy-dense food is supposed to (partially) explain why these foods are over-consumed despite of detrimental health consequences. In Study Β we investigated food responsiveness in patients who had undergone Roux-en-Y gastric bypass surgery to overcome excessive obesity. This type of gastric bypass surgery is not only known to alter food appreciation, but also the secretion patterns of adipokines and gut peptides. Study Β aimed at a comprehensive and interdisciplinary investigation of differences along the gut-brain axis in bypass-operated patients as opposed to weight-matched non-operated controls. On the one hand, the spatio-temporal brain dynamics to the visual perception of high- vs. low-energy foods under differing states of motivation towards food intake (i.e. pre- and post-prandial) were assessed and compared between groups. On the other hand, peripheral gut hormone measures were taken in pre- and post-prandial nutrition state and compared between groups. In order to evaluate alterations in the responsiveness along the gut-brain-axis related to gastric bypass surgery, correlations between both measures were compared between both participant groups. The results revealed that Roux-en- Y gastric bypass surgery alters the spatio-temporal brain dynamics to the perception of high- and low-energy food cues, as well as the responsiveness along the gut-brain-axis. The potential role of these response alterations is discussed in relation to previously observed changes in physiological factors and food intake behavior post-Roux-en-Y gastric bypass surgery. By doing so, we highlight potential behavioral, neural and endocrine (i.e. gut hormone) targets for the future development of intervention strategies for deviant eating behavior and obesity. Together, the studies showed that the visual representation of foods in the brain is plastic and that modulations in neural activity are already noted at early stages of visual processing. Different factors of influence such as a repeated exposure, Roux-en-Y gastric bypass surgery, motivation (nutrition state), as well as the energy density of the visually perceived food were identified. En raison de la prévalence croissante de l'obésité et du défi que cela représente en matière de santé publique, une meilleure compréhension des processus comportementaux et cérébraux liés à la nourriture sont nécessaires. En particulier, cette thèse se concentre sur l'investigation des mécanismes cérébraux spatio-temporels liés à la perception visuelle de la nourriture. Nous sommes quotidiennement et répétitivement exposés à des images de nourriture. Ces expositions répétées influencent nos choix, ainsi que nos préférences alimentaires. La première étude (Study A) de cette thèse investigue donc l'impact de ces exposition répétée à des stimuli visuels de nourriture. En particulier, nous avons comparé la dynamique spatio-temporelle de l'activité cérébrale induite par une exposition répétée à des images de nourriture de haute densité et de basse densité énergétique. (Manuscrit publié: "The role of energetic value in dynamic brain response adaptation during repeated food image viewing" (Lietti et al., 2012)). Dans cette étude, nous avons pu constater qu'une exposition répétée à des images représentant de la nourriture de haute densité énergétique, par opposition à de la nourriture de basse densité énergétique, affecte les mécanismes comportementaux et cérébraux de manière différente. En particulier, la représentation neurale des images de nourriture de haute densité énergétique est similaire lors de l'exposition initiale que lors de l'exposition répétée. Ceci indique que la perception d'images de nourriture de haute densité énergétique induit des adaptations comportementales et neurales de moindre ampleur par rapport à la perception d'images de nourriture de basse densité énergétique ou à la perception d'une « catégorie contrôle » d'objets qui ne sont pas de la nourriture. Notre discussion est orientée sur les notions prépondérantes de récompense et de motivation qui sont associées à la nourriture de haute densité énergétique. Nous suggérons que la nourriture de haute densité énergétique génère une représentation mémorielle plus stable et que ce mécanisme pourrait (partiellement) être sous-jacent au fait que la nourriture de haute densité énergétique soit préférentiellement consommée. Dans la deuxième étude (Study Β) menée au cours de cette thèse, nous nous sommes intéressés aux mécanismes de perception de la nourriture chez des patients ayant subi un bypass gastrique Roux- en-Y, afin de réussir à perdre du poids et améliorer leur santé. Ce type de chirurgie est connu pour altérer la perception de la nourriture et le comportement alimentaire, mais également la sécrétion d'adipokines et de peptides gastriques. Dans une approche interdisciplinaire et globale, cette deuxième étude investigue donc les différences entre les patients opérés et des individus « contrôles » de poids similaire au niveau des interactions entre leur activité cérébrale et les mesures de leurs hormones gastriques. D'un côté, nous avons investigué la dynamique spatio-temporelle cérébrale de la perception visuelle de nourriture de haute et de basse densité énergétique dans deux états physiologiques différent (pre- et post-prandial). Et de l'autre, nous avons également investigué les mesures physiologiques des hormones gastriques. Ensuite, afin d'évaluer les altérations liées à l'intervention chirurgicale au niveau des interactions entre la réponse cérébrale et la sécrétion d'hormone, des corrélations entre ces deux mesures ont été comparées entre les deux groupes. Les résultats révèlent que l'intervention chirurgicale du bypass gastrique Roux-en-Y altère la dynamique spatio-temporelle de la perception visuelle de la nourriture de haute et de basse densité énergétique, ainsi que les interactions entre cette dernière et les mesures périphériques des hormones gastriques. Nous discutons le rôle potentiel de ces altérations en relation avec les modulations des facteurs physiologiques et les changements du comportement alimentaire préalablement déjà démontrés. De cette manière, nous identifions des cibles potentielles pour le développement de stratégies d'intervention future, au niveau comportemental, cérébral et endocrinien (hormones gastriques) en ce qui concerne les déviances du comportement alimentaire, dont l'obésité. Nos deux études réunies démontrent que la représentation visuelle de la nourriture dans le cerveau est plastique et que des modulations de l'activité neurale apparaissent déjà à un stade très précoce des mécanismes de perception visuelle. Différents facteurs d'influence comme une exposition repetee, le bypass gastrique Roux-en-Y, la motivation (état nutritionnel), ainsi que la densité énergétique de la nourriture qui est perçue ont pu être identifiés.

Epidermal growth factor enhances the expression of an endogenous lectin in aggregating fetal brain cell cultures.

Aggregating cell cultures prepared from fetal rat telencephalon express the two subunits [cerebellar soluble lectins (CSL) 1 and 2] of a soluble, mannose-specific endogenous lectin (CSL) in a development-dependent manner. Increased CSL synthesis was found at an early postmitotic stage as well as during the period of maximal myelination. Repetitive treatment of early cultures with epidermal growth factor (EGF, 3nM) caused a great stimulation of CSL biosynthesis. Immunocytochemical studies revealed particularly intense CSL-specific staining in small, EGF-responsive cells, presumably glial cells. Large quantities of CSL-immunoreactive material were found also in the extracellular space and on the external side of the plasma membrane, indicating abundant release of CSL. The present findings suggest that EGF or EGF-related factors in the brain are able to regulate the expression of an endogenous lectin, affecting brain ontogeny.

Aggregating brain cell cultures for neurotoxicological studies.

Because of the limited accessibility of the brain for experimentation, but also for ethical and economical reasons, there is considerable interest in culture models suitable for neurotoxicological research. Although it is generally accepted that in vitro models cannot cover the entire spectrum of brain functions, they have proven to be indispensable for investigations in the life sciences since the early work of Harrison (1). To date, many in vitro models of various complexity are available, ranging from monolayer cultures of immortalized cell lines to organotypic cultures. Each of these culture systems has its particularities, therefore, it is of great importance to select the model that is most appropriate for the question to be solved.

FXYD7 is a brain-specific regulator of Na,K-ATPase alpha 1-beta isozymes.

Recently, corticosteroid hormone-induced factor (CHIF) and the gamma-subunit, two members of the FXYD family of small proteins, have been identified as regulators of renal Na,K-ATPase. In this study, we have investigated the tissue distribution and the structural and functional properties of FXYD7, another family member which has not yet been characterized. Expressed exclusively in the brain, FXYD7 is a type I membrane protein bearing N-terminal, post-translationally added modifications on threonine residues, most probably O-glycosylations that are important for protein stabilization. Expressed in Xenopus oocytes, FXYD7 can interact with Na,K-ATPase alpha 1-beta 1, alpha 2-beta 1 and alpha 3-beta 1 but not with alpha-beta 2 isozymes, whereas, in brain, it is only associated with alpha 1-beta isozymes. FXYD7 decreases the apparent K(+) affinity of alpha 1-beta 1 and alpha 2-beta 1, but not of alpha 3-beta1 isozymes. These data suggest that FXYD7 is a novel, tissue- and isoform-specific Na,K-ATPase regulator which could play an important role in neuronal excitability.

Revue critique d'instruments pour evaluer la douleur chez les personnes cérébrolésées non communicantes aux soins intensifs [Critical review of instruments to assess pain in the non communicative brain injured persons in intensive care].

The purpose of this review is to critically appraise the pain assessment tools for non communicative persons in intensive care available in the literature and to determine their relevance for those with brain injury. Nursing and medical electronic databases were searched to identify pain tools, with a description of psychometric proprieties, in English and French. Seven of the ten tools were considered relevant and systematically evaluated according to the criteria and the indicators in the following five areas: conceptualisation, target population, feasibility and clinical utility, reliability and validity. Results indicate a number of well designed pain tools, but additional work is necessary to establish their accuracy and adequacy for the brain injured non communicative person in intensive care. Recommendations are made to choose the best tool for clinical practice and for research.

Serum and CSF levels of neuron-specific enolase (NSE) in cardiac surgery with cardiopulmonary bypass: a marker of brain injury?

We investigated whether neuron-specific enolase (NSE) in serum or cerebrospinal fluid (CSF) reflects subtle or manifest brain injury in children undergoing cardiac surgery using cardiopulmonary bypass (CPB). NSE was measured in serum (s-NSE) before, and up to, 102 h after surgery in 27 children undergoing cardiac surgery with CPB. In 11 children, CSF-NSE was also measured 48 or 66 h post-surgery. As erythrocytes contain NSE, hemoglobin concentration in the samples was determined spectrophotometrically at 550 nm (cut-off limit: absorbance 0.4 = 560 mg/l) in 14 children and in a further 13 children by spectroscopic multicomponent analysis (cut-off limit 5 micromol/l = 80 mg/l). One hundred and one of 214 post-operative serum samples (47%) had to be discarded because of hemolysis (18% spectrophotometrically at 550 nm and 88% with spectroscopic multicomponent analysis). On the first and second post-operative day, the median s-NSE values were significantly higher when compared with samples taken after 54 h or longer (P = 0.008 and P = 0.002). All CSF-NSE levels were within the normal range and below the s-NSE measured in the same patient. Although in our study elevated s-NSE seems to indicate brain injury in CPB-surgery, the low concentration of NSE in the post-operative CSF of 11 children puts the neuronal origin of s-NSE in question. NSE from other non-neuronal tissues probably contributes to the elevated s-NSE. Additionally, normal post-operative CSF-NSE values in two children with post-operative neurological sequelae might question the predictive value of CSF-NSE with regard to brain injury.

Evaluation of aggregating brain cell cultures for the detection of acute organ-specific toxicity.

As part of the ACuteTox project aimed at the development of non-animal testing strategies for predicting human acute oral toxicity, aggregating brain cell cultures (AGGR) were examined for their capability to detect organ-specific toxicity. Previous multicenter evaluations of in vitro cytotoxicity showed that some 20% of the tested chemicals exhibited significantly lower in vitro toxicity as expected from in vivo toxicity data. This was supposed to be due to toxicity at supracellular (organ or system) levels. To examine the capability of AGGR to alert for potential organ-specific toxicants, concentration-response studies were carried out in AGGR for 86 chemicals, taking as endpoints the mRNA expression levels of four selected genes. The lowest observed effect concentration (LOEC) determined for each chemical was compared with the IC20 reported for the 3T3/NRU cytotoxicity assay. A LOEC lower than IC20 by at least a factor of 5 was taken to alert for organ-specific toxicity. The results showed that the frequency of alerts increased with the level of toxicity observed in AGGR. Among the chemicals identified as alert were many compounds known for their organ-specific toxicity. These findings suggest that AGGR are suitable for the detection of organ-specific toxicity and that they could, in conjunction with the 3T3/NRU cytotoxicity assay, improve the predictive capacity of in vitro toxicity testing.

Effects of MRI scan acceleration on brain volume measurement consistency.

PURPOSE: To evaluate the effects of recent advances in magnetic resonance imaging (MRI) radiofrequency (RF) coil and parallel imaging technology on brain volume measurement consistency. MATERIALS AND METHODS: In all, 103 whole-brain MRI volumes were acquired at a clinical 3T MRI, equipped with a 12- and 32-channel head coil, using the T1-weighted protocol as employed in the Alzheimer's Disease Neuroimaging Initiative study with parallel imaging accelerations ranging from 1 to 5. An experienced reader performed qualitative ratings of the images. For quantitative analysis, differences in composite width (CW, a measure of image similarity) and boundary shift integral (BSI, a measure of whole-brain atrophy) were calculated. RESULTS: Intra- and intersession comparisons of CW and BSI measures from scans with equal acceleration demonstrated excellent scan-rescan accuracy, even at the highest acceleration applied. Pairs-of-scans acquired with different accelerations exhibited poor scan-rescan consistency only when differences in the acceleration factor were maximized. A change in the coil hardware between compared scans was found to bias the BSI measure. CONCLUSION: The most important findings are that the accelerated acquisitions appear to be compatible with the assessment of high-quality quantitative information and that for highest scan-rescan accuracy in serial scans the acquisition protocol should be kept as consistent as possible over time. J. Magn. Reson. Imaging 2012;36:1234-1240. ©2012 Wiley Periodicals, Inc.