Nathalie Just

Minimization of Nyquist ghosting for echo-planar imaging at ultra-high fields based on a "negative readout gradient" strategy

To improve the traditional Nyquist ghost correction approach in echo planar imaging (EPI) at high fields, via schemes based on the reversal of the EPI readout gradient polarity for every other volume throughout a functional magnetic resonance imaging (fMRI) acquisition train.

Compartmentalised energy metabolism supporting glutamatergic neurotransmission in response to increased activity in the rat cerebral cortex: A 13C MRS study in vivo at 14.1 T

Many tissues exhibit metabolic compartmentation. In the brain, while there is no doubt on the importance of functional compartmentation between neurons and glial cells, there is still debate on the specific regulation of pathways of energy metabolism at different activity levels. Using 13C magnetic resonance spectroscopy (MRS) in vivo, we determined fluxes of energy metabolism in the rat cortex under α-chloralose anaesthesia at rest and during electrical stimulation of the paws. Compared to resting metabolism, the stimulated rat cortex exhibited increased glutamate–glutamine cycle (+67 nmol/g/min, +95%, P < 0.001) and tricarboxylic (TCA) cycle rate in both neurons (+62 nmol/g/min, +12%, P < 0.001) and astrocytes (+68 nmol/g/min, +22%, P = 0.072). A minor, non-significant modification of the flux through pyruvate carboxylase was observed during stimulation (+5 nmol/g/min, +8%). Altogether, this increase in metabolism amounted to a 15% (67 nmol/g/min, P < 0.001) increase in CMRglc(ox), i.e. the oxidative fraction of the cerebral metabolic rate of glucose. In conclusion, stimulation of the glutamate–glutamine cycle under α-chloralose anaesthesia is associated to similar enhancement of neuronal and glial oxidative metabolism.

Characterization of sustained BOLD activation in the rat barrel cortex and neurochemical consequences

To date, only a couple of functional MR spectroscopy (fMRS) studies were conducted in rats. Due to the low temporal resolution of (1)H MRS techniques, prolonged stimulation paradigms are necessary for investigating the metabolic outcome in the rat brain during functional challenge. However, sustained activation of cortical areas is usually difficult to obtain due to neural adaptation. Anesthesia, habituation, high variability of the basal state metabolite concentrations as well as low concentrations of the metabolites of interest such as lactate (Lac), glucose (Glc) or γ-aminobutyric acid (GABA) and small expected changes of metabolite concentrations need to be addressed. In the present study, the rat barrel cortex was reliably and reproducibly activated through sustained trigeminal nerve (TGN) stimulation. In addition, TGN stimulation induced significant positive changes in lactate (+1.01 μmol/g, p<0.008) and glutamate (+0.92 μmol/g, p<0.02) and significant negative aspartate changes (-0.63 μmol/g, p<0.004) using functional (1)H MRS at 9.4 T in agreement with previous changes observed in human fMRS studies. Finally, for the first time, the dynamics of lactate, glucose, aspartate and glutamate concentrations during sustained somatosensory activation in rats using fMRS were assessed. These results allow demonstrating the feasibility of fMRS measurements during prolonged barrel cortex activation in rats.

BOLD responses to trigeminal nerve stimulation

The current study investigates a new model of barrel cortex activation using stimulation of the infraorbital branch of the trigeminal nerve. A robust and reproducible activation of the rat barrel cortex was obtained following trigeminal nerve stimulation. Blood oxygen level-dependent (BOLD) effects were obtained in the primary somatosensory barrel cortex (S1BF), the secondary somatosensory cortex (S2) and the motor cortex. These cortical areas were reached from afferent pathways from the trigeminal ganglion, the trigeminal nuclei and thalamic nuclei from which neurons project their axons upon whisker stimulation. The maximum BOLD responses were obtained for a stimulus frequency of 1 Hz, a stimulus pulse width of 100 μs and for current intensities between 1.5 and 3 mA. The BOLD response was nonlinear as a function of frequency and current intensity. Additionally, modeling BOLD responses in the rat barrel cortex from separate cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO(2)) measurements showed good agreement with the shape and amplitude of measured BOLD responses as a function of stimulus frequency and will potentially allow to identify the sources of BOLD nonlinearities. Activation of the rat barrel cortex using trigeminal nerve stimulation will contribute to the interpretation of the BOLD signals from functional magnetic resonance imaging studies.

Assessment of the effect of haematocrit-dependent arterial input functions on the accuracy of pharmacokinetic parameters in dynamic contrast-enhanced MRI

The detection and prognosis of prostate cancer in its early stages are critically important. It is therefore essential to improve the existing dynamic contrast‐enhanced MRI (DCE MRI) techniques commonly used for the assessment of the tumour vascular environment. The goal of this study was to describe a method for the estimation of the arterial input function (AIF) in DCE MRI by measuring R2* values in the femoral artery of patients with early‐stage prostate cancer. The calculation of contrast agent concentrations was based on calibration curves determined in whole blood samples for a range of normal haematocrit (HCT) values (HCT = 0.35–0.525). Individual AIFs corrected for HCT were compared with individual AIFs calibrated with a mean whole blood [R2*–Gd‐DTPA‐BMA] [Gd‐DTPA‐BMA, gadolinium diethylenetriaminepentaacetate‐bis(methylamide) (gadodiamide)] curve at an assumed HCT = 0.44, as well as a population AIF at an assumed HCT = 0.45. The area under the curve of the first‐pass bolus ranged between 0.6 min mM at HCT = 0.53 and 1.3 min mM at HCT = 0.39. Significant differences in magnitude at peak contrast agent concentrations (HCT = 0.36, [Gd‐DTPA‐BMA]max = 9 ± 0.4 mM; HCT = 0.46, [Gd‐DTPA‐BMA]max = 4.0 ± 0.2 mM) were found. Using model‐based simulations, the accuracy of the kinetic parameters estimated using individual AIFs corrected for HCT demonstrated that, for the use of individual calibration curves with HCT values differing by more than 10%, Ktrans and kep values were largely underestimated (up to 60% difference for Ktrans). Moreover, blood volume estimates were severely underestimated. Estimates of kinetic parameters in early‐stage prostate cancer patients demonstrated that the efflux rate constant (kep) was influenced significantly by the definition of AIF. Regardless of whether an individually calibrated AIF or a population AIF (average of all individually calibrated AIFs) was used, pixel‐by‐pixel mapping of kep and vb in the prostate gland appeared to be more sensitive than with the usual biexponential approach. Copyright

Effect of manganese chloride on the neurochemical profile of the rat hypothalamus.

Manganese (Mn2+)-enhanced magnetic resonance imaging studies of the neuronal pathways of the hypothalamus showed that information about the regulation of food intake and energy balance circulate through specific hypothalamic nuclei. The dehydration-induced anorexia (DIA) model demonstrated to be appropriate for studying the hypothalamus with Mn2+-enhanced magnetic resonance imaging. Manganese is involved in the normal functioning of a variety of physiological processes and is associated with enzymes contributing to neurotransmitter synthesis and metabolism. It also induces psychiatric and motor disturbances. The molecular mechanisms by which Mn2+ produces alterations of the hypothalamic physiological processes are not well understood. 1H-magnetic resonance spectroscopy measurements of the rodent hypothalamus are challenging due to the distant location of the hypothalamus resulting in limited measurement sensitivity. The present study proposed to investigate the effects of Mn2+ on the neurochemical profile of the hypothalamus in normal, DIA, and overnight fasted female rats at 14.1 T. Results provide evidence that γ-aminobutyric acid has an essential role in the maintenance of energy homeostasis in the hypothalamus but is not condition specific. On the contrary, glutamine, glutamate, and taurine appear to respond more accurately to Mn2+ exposure. An increase in glutamine levels could also be a characteristic response of the hypothalamus to DIA.

Imaging of prolonged BOLD response in the somatosensory cortex of the rat

Blood oxygenation level‐dependent (BOLD) functional MRI is a widely employed methodology in experimental and clinical neuroscience, although its nature is not fully understood. To gain insights into BOLD mechanisms and take advantage of the new functional methods, it is of interest to investigate prolonged paradigms of activation suitable for long experimental protocols and to observe any long‐term modifications induced by these functional challenges. While different types of sustained stimulation paradigm have been explored in human studies, the BOLD response is typically limited to a few minutes in animal models, due to fatigue, anesthesia effects and physiological instability. In the present study, the rat forepaw was electrically stimulated for 2 h, which resulted in a prolonged and localized cortical BOLD response over that period. The stimulation paradigm, including an inter‐stimulus interval (ISI) of 10 s, that is 25% of the total time, was applied at constant or variable frequency over 2 h. The steady‐state level of the BOLD response was reached after 15–20 min of stimulation and was maintained until the end of the stimulation. On average, no substantial loss in activated volume was observed at the end of the stimulation, but less variability in the fraction of remaining activated volume and higher steady‐state BOLD amplitude were observed when stimulation frequency was varied between 2 and 3 Hz every 5 min. We conclude that the combination of ISI and variable stimulus frequency reproducibly results in robust, prolonged and localized BOLD activation. Copyright

Histogram Analysis of the Microvasculature of Intracerebral Human and Murine Glioma Xenografts

The purpose of this study is to examine the usefulness of histogram analysis combined with vessel size index (VSI) magnetic resonance imaging for the specific characterization of brain tumor microvasculature in a panel of six volume‐matched glioma xenografts. Using a simple descriptive histogram analysis, significant differences of the mean tumoral VSI (P = 0.0035 for 9L, P = 0.008 for glioma mix, P = 0.05 for C6), the 75th VSI percentile (P = 0.003–0.075) as well as the 25th and median blood volume (BV) percentiles were found in murine gliomas compared to their contralateral healthy brain. Using a segmented histogram analysis, dilatation of already existing vessels in murine gliomas and development of new small caliber vessels in human glioblastomas were suggested. Most gliomas showed a higher proportion of pixels with BV below 1% (glioma mix [21% vs 1%], Glioblastoma 2 (GBM2) [9% vs 3.7%]) and a smaller proportion of pixels with BV in the range 1.7–6.3% (65 vs 90% for glioma mix, 80 vs 85% in GBM2) relative to their contralateral part. In glioblastomas, VSI and BV distributions were similar to normal brain distributions and in agreement with immunohistochemical findings. The histogram analysis of VSI and BV heterogeneity in experimental brain tumors allowed detection of microregional differences in gliomas from different origins. Magn Reson Med, 2011.

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 1H MRS at 14.1 T. 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 1H 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. Copyright

Snapshot gradient-recalled echo-planar images of rat brains at long echo time at 9.4 T

With improved B 0 homogeneity along with satisfactory gradient performance at high magnetic fields, snapshot gradient-recalled echo-planar imaging (GRE-EPI) would perform at long echo times (TEs) on the order of T2*, which intrinsically allows obtaining strongly T2*-weighted images with embedded substantial anatomical details in ultrashort time. The aim of this study was to investigate the feasibility and quality of long TE snapshot GRE-EPI images of rat brain at 9.4 T. When compensating for B 0 inhomogeneities, especially second-order shim terms, a 200 x 200 microm2 in-plane resolution image was reproducibly obtained at long TE (>25 ms). The resulting coronal images at 30 ms had diminished geometric distortions and, thus, embedded substantial anatomical details. Concurrently with the very consistent stability, such GRE-EPI images should permit to resolve functional data not only with high specificity but also with substantial anatomical details, therefore allowing coregistration of the acquired functional data on the same image data set.