Rolf F. Schulte

GABA concentrations in the human anterior cingulate cortex predict negative BOLD responses in fMRI

The human anterior cingulate cortex (ACC) is part of the default-mode network that shows predominant negative blood oxygen level–dependent (BOLD) responses in functional magnetic resonance imaging (fMRI). We combined fMRI during emotional processing and resting-state magnetic resonance spectroscopy measurements and observed that the concentration of GABA in the ACC specifically correlated with the amount of negative BOLD responses in the very same region. Our findings show that default-mode network negative BOLD responses during emotions are mediated by GABA.

The Relationship Between Aberrant Neuronal Activation in the Pregenual Anterior Cingulate, Altered Glutamatergic Metabolism, and Anhedonia in Major Depression

CONTEXT Major depressive disorder (MDD) is characterized by diverse metabolic and functional abnormalities that occur in, among other regions, the pregenual anterior cingulate cortex (pgACC), a cortical region linked to anhedonia. OBJECTIVES To contextualize metabolic, functional, and clinical parameters and thus to reveal cellular mechanisms related to anhedonia. DESIGN The pgACC was investigated using a combined functional magnetic resonance imaging and magnetic resonance spectroscopic approach. Negative blood oxygenation level-dependent (BOLD) activations in the pgACC were assessed during emotional stimulation. Quantitative J-resolved magnetic resonance spectroscopy in the pgACC enabled simultaneous determination of glutamine, glutamate, N-acetylaspartate, glucose, and gamma-aminobutyric acid concentrations. Subjective emotional intensity ratings as well as various clinical parameters were determined. SETTING The patients were recruited and evaluated in the Department of Psychiatry, University of Zurich, while the measurements were performed in the Institute of Biomedical Engineering, University of Zurich and the Technical University Zurich. PARTICIPANTS Nineteen unmedicated patients with MDD and 24 healthy subjects. MAIN OUTCOME MEASURES Reduced glutamine levels and lower functional responses in pgACC in anhedonic depressed patients were expected to be the predominant effect of abnormal glutamatergic transmission. It was further tested if, among patients, the ratings of emotional intensity on visual stimulation predicted the amount of metabolic and functional alterations in terms of reduced relative metabolite concentrations and BOLD changes. RESULTS Patients with highly anhedonic MDD show decreased glutamine but normal glutamate and gamma-aminobutyric acid concentrations, with glutamine concentrations being dissociated from glucose concentrations. Glutamate and N-acetylaspartate concentrations in pgACC correlate with negative BOLD responses induced by emotional stimulation in MDD; whereas in healthy subjects, negative BOLD responses correlate with gamma-aminobutyric acid instead. Negative BOLD responses as well as glutamate and N-acetylaspartate concentrations correlate with emotional intensity ratings, an anhedonia surrogate, in those with MDD but not in healthy subjects. CONCLUSION Aberrant neuronal activation patterns of the pgACC in anhedonic depression are related to deficits of glutamatergic metabolism.

IDEAL spiral CSI for dynamic metabolic MR imaging of hyperpolarized [1‐13C]pyruvate

Metabolic imaging with hyperpolarized [1‐13C]pyruvate offers the unique opportunity for a minimally invasive detection of cellular metabolism. Efficient and robust acquisition and reconstruction techniques are required for capturing the wealth of information present for the limited duration of the hyperpolarized state (∼1 min). In this study, the Dixon/IDEAL type of water–fat separation is expanded toward spectroscopic imaging of [1‐13C]pyruvate and its down‐stream metabolites. For this purpose, the spectral–spatial encoding is based on single‐shot spiral image encoding and echo‐time shifting in between excitations for the chemical‐shift encoding. In addition, also a free‐induction decay spectrum is acquired and the obtained chemical‐shift prior knowledge is efficiently used in the reconstruction. The spectral–spatial reconstruction problem is found to efficiently separate into a chemical‐shift inversion followed by a spatial reconstruction. The method is successfully demonstrated for dynamic, multislice [1‐13C]pyruvate metabolic MR imaging in phantom and in vivo rat experiments. Magn Reson Med, 2012.

Saturation-recovery metabolic-exchange rate imaging with hyperpolarized [1-13C] pyruvate using spectral-spatial excitation.

Within the last decade hyperpolarized [1‐13C] pyruvate chemical‐shift imaging has demonstrated impressive potential for metabolic MR imaging for a wide range of applications in oncology, cardiology, and neurology. In this work, a highly efficient pulse sequence is described for time‐resolved, multislice chemical shift imaging of the injected substrate and obtained downstream metabolites. Using spectral‐spatial excitation in combination with single‐shot spiral data acquisition, the overall encoding is evenly distributed between excitation and signal reception, allowing the encoding of one full two‐dimensional metabolite image per excitation. The signal‐to‐noise ratio can be flexibly adjusted and optimized using lower flip angles for the pyruvate substrate and larger ones for the downstream metabolites. Selectively adjusting the excitation of the down‐stream metabolites to 90° leads to a so‐called “saturation‐recovery” scheme with the detected signal content being determined by forward conversion of the available pyruvate. In case of repetitive excitations, the polarization is preserved using smaller flip angles for pyruvate. Metabolic exchange rates are determined spatially resolved from the metabolite images using a simplified two‐site exchange model. This novel contrast is an important step toward more quantitative metabolic imaging. Goal of this work was to derive, analyze, and implement this “saturation‐recovery metabolic exchange rate imaging” and demonstrate its capabilities in four rats bearing subcutaneous tumors. Magn Reson Med, 2013.

Experimental validation of the hyperpolarized (129) Xe chemical shift saturation recovery technique in healthy volunteers and subjects with interstitial lung disease.

To assess the sensitivity of the hyperpolarized 129Xe chemical shift saturation recovery (CSSR) technique for noninvasive quantification of changes to lung microstructure and function in idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc).

Diffusion of hyperpolarized 13C-metabolites in tumor cell spheroids using real-time NMR spectroscopy

The detection of tumors noninvasively, the characterization of their progression by defined markers and the monitoring of response to treatment are goals of medical imaging techniques. In this article, a method which measures the apparent diffusion coefficients (ADCs) of metabolites using hyperpolarized 13C diffusion‐weighted spectroscopy is presented. A pulse sequence based on the pulsed gradient spin echo (PGSE) was developed that encodes both kinetics and diffusion information. In experiments with MCF‐7 human breast cancer cells, we detected an ADC of intracellularly produced lactate of 1.06 ± 0.15 µm2/ms, which is about one‐half of the value measured with pyruvate in extracellular culture medium. When monitoring tumor cell spheroids during progressive membrane permeabilization with Triton X‐100, the ratio of lactate ADC to pyruvate ADC increases as the fraction of dead cells increases. Therefore, 13C ADC detection can yield sensitive information on changes in membrane permeability and subsequent cell death. Our results suggest that both metabolic label exchange and 13C ADCs can be acquired simultaneously, and may potentially serve as noninvasive biomarkers for pathological changes in tumor cells. Copyright

SELOVS: Brain MRSI localization based on highly selective T1- and B1-insensitive outer-volume suppression at 3T

In vivo, high‐field MR spectroscopic imaging (MRSI) profits from signal‐to‐noise ratio (SNR) gain and increased spectral resolution. However, bandwidth limitations of slice‐selective excitation and refocusing pulses lead to strong chemical‐shift displacement at high field strength when using conventional MRSI localization based on PRESS. Consequential metabolic information, particularly of border regions such as cortical brain tissue, is distorted. In addition, lipid contamination remains a major confound. To address these problems it is proposed to abandon PRESS selection and rely on a novel scheme of highly selective T1‐ and B1‐insensitive outer‐volume suppression in combination with slice‐selective spin‐echo acquisition for brain MRSI. Multiple cycles of overlapping suppression slabs are applied with flip angles optimized to account for tissue‐dependent T1 relaxation times and band crossings. Broadband frequency modulated saturation pulses with polynomial phase‐response are utilized in order to minimize chemical‐shift displacement. Efficacy of the outer‐volume suppression sequence was simulated and evaluated in vitro and in vivo. Brain MRSI localization at 3T was significantly improved and reliable suppression of short‐range lipid contamination enabled, leading to substantial enhancement of spectral quality, particularly in cortical tissue. Hence, the new method holds potential to expand the applicability of high‐field MRSI to the entire brain. Magn Reson Med, 2007.

Multi-Channel Metabolic Imaging, with SENSE reconstruction, of Hyperpolarized [1-13C] Pyruvate in a Live Rat at 3.0 tesla on a Clinical MR Scanner

We report metabolic images of (13)C, following injection of a bolus of hyperpolarized [1-(13)C] pyruvate in a live rat. The data were acquired on a clinical scanner, using custom coils for volume transmission and array reception. Proton blocking of all carbon resonators enabled proton anatomic imaging with the system body coil, to allow for registration of anatomic and metabolic images, for which good correlation was achieved, with some anatomic features (kidney and heart) clearly visible in a carbon image, without reference to the corresponding proton image. Parallel imaging with sensitivity encoding was used to increase the spatial resolution in the SI direction of the rat. The signal to noise ratio in was in some instances unexpectedly high in the parallel images; variability of the polarization among different trials, plus partial volume effects, are noted as a possible cause of this.

A comparison of quantitative methods for clinical imaging with hyperpolarized 13C-pyruvate

Dissolution dynamic nuclear polarization (DNP) enables the metabolism of hyperpolarized 13C‐labelled molecules, such as the conversion of [1‐13C]pyruvate to [1‐13C]lactate, to be dynamically and non‐invasively imaged in tissue. Imaging of this exchange reaction in animal models has been shown to detect early treatment response and correlate with tumour grade. The first human DNP study has recently been completed, and, for widespread clinical translation, simple and reliable methods are necessary to accurately probe the reaction in patients. However, there is currently no consensus on the most appropriate method to quantify this exchange reaction. In this study, an in vitro system was used to compare several kinetic models, as well as simple model‐free methods. Experiments were performed using a clinical hyperpolarizer, a human 3 T MR system, and spectroscopic imaging sequences. The quantitative methods were compared in vivo by using subcutaneous breast tumours in rats to examine the effect of pyruvate inflow. The two‐way kinetic model was the most accurate method for characterizing the exchange reaction in vitro, and the incorporation of a Heaviside step inflow profile was best able to describe the in vivo data. The lactate time‐to‐peak and the lactate‐to‐pyruvate area under the curve ratio were simple model‐free approaches that accurately represented the full reaction, with the time‐to‐peak method performing indistinguishably from the best kinetic model. Finally, extracting data from a single pixel was a robust and reliable surrogate of the whole region of interest. This work has identified appropriate quantitative methods for future work in the analysis of human hyperpolarized 13C data.

ProFit revisited: ProFit Revisited

An enhanced version of the ProFit fitting tool was developed and validated to improve the quantification of two‐dimensional JRPESS spectroscopic data.