Fields of expertise
Magnetic resonance imaging
Mathematical models of metabolism
Neuroscience of hypoglycemia
In vivo kinetics
1999 Young Investigator Award Plenary Lectureship, International Society for Neurochemistry
2011 Fellow, ESMRMB
2011 Teaching Award, Section Sciences de la Vie, EPFL
TeachingFundamentals of biomedical imaging (Master, SPH, SSV, Mineurs) - spring semester, on moodle & filmed, since Feb. 2006
Physique générale I SV (SSV) - fall semester (moodle), since Sept. 2009
Advanced biomedical imaging methods and instrumentation (EDPY) - Fall semester, since Sept. 2006
Minor contributions to courses:
Neuroscience for engineers (SSV)- spring semester (moodle)
Molecular pahtology and therapy of neurodegenerative diseass (EDNE)
Editorial BoardsEditorial Board, Journal of Neuroscience Research (2001 present)
Editorial Board, Magma (2003 present)
Editorial Board, Neurochemical Research (2003 present)
Editorial Board, ASN Neuro
Associate Editor, Frontiers in Neuroenergetics
Deputy Editor, Magnetic Resonance in Medicine (1999-2011)
Editorial Board, NMR in Biomedicine (2003 2011)
Editorial Board, Magnetic Resonance in Medicine (2001- 2004)
Reviewing activity: JournalsAm. J. Physiol. (Metabolism and Endocrinology)
Am. J. Physiol. (Integrative and Comparative)
Am. J. Physiol. (Cell Physiology)
Brain Res. Bull.
Brain Res. Rev.
Eur. J. Pediatrics
Eur. J. Neurosci.
J. Cereb. Blood Flow Metab.
J. Magn. Reson.,
J. Neurosci. Res.
Magn. Reson. Med.,
Proc. Natl. Acad. Sci. USA,
Trends in Neuroscienes
Grant Review BoardsNational Institute of Health
ad hoc member
NINDS, study section NSD-B / NSD-C ad hoc member
NIDA ad hoc member, Special Emphasis Panels
NIDDK ad hoc member, special emphasis panel
National Science bodies
Fonds National Suisse
Dutch Science Foundation
National Science Foundation (US)
Binational Science Foundation
Alzheimer Disease Foundation
Diabetes Foundation Netherlands
Juvenile Diabetes Research Foundation International
List of publicationsIs provided here
ImpactCitation rates 2000-2010
Shown is number of citations per published item (articles & reviews, source ISI), amounting to 106 publications over the period 2000-2010.
Indicated in parentheses is the next best field (i.e. having a lower average citation rate) and its rank of 21 disciplines (see for comparison here )
2000: 52.0 (1. Molecular Biology)
2001: 54.7 (1. Molecular Biology)
2002: 34.2 (2. Immunology)
2003: 46.2 (1. Molecular Biology)
2004: 39.5 (1. Molecular Biology)
2005: 14.3 (8. Pharmacology)
2006: 14.9 (4. Biochemistry)
2007: 13.7 (3. Neuroscience)
2008: 6.7 (7. Clinical Medicine)
2009: 5.0 (4. Neuroscience)
2010: 0.4 (10. Physics)
Average citations/item covering the period 2000-2010 : 20.2 (3. Neuroscience)
QRED analysis : 16 publications in 2009, on average cited 4.9 times in 2010 : Q >>100%
Last 5 years
 Radical-free hyperpolarized MRI using endogenously occurring pyruvate analogues and UV-induced nonpersistent radicalsNmr In Biomedicine. 2021-07-10. DOI : 10.1002/nbm.4584.
 Measuring Glycolytic Activity with Hyperpolarized [2H7, U-13C6] D-Glucose in the Naive Mouse Brain under Different Anesthetic ConditionsMetabolites. 2021-06-23. DOI : 10.3390/metabo11070413.
 Dipole-Fed Rectangular Dielectric Resonator Antennas for Magnetic Resonance Imaging at 7 T: The Impact of Quasi-Transverse Electric Modes on Transmit Field DistributionFrontiers In Physics. 2021-06-15. DOI : 10.3389/fphy.2021.675509.
 PIRACY: An Optimized Pipeline for Functional Connectivity Analysis in the Rat BrainFrontiers In Neuroscience. 2021-03-26. DOI : 10.3389/fnins.2021.602170.
 Hyperpolarized C-13-glucose magnetic resonance highlights reduced aerobic glycolysis in vivo in infiltrative glioblastomaScientific Reports. 2021-03-11. DOI : 10.1038/s41598-021-85339-7.
 The relationship between EEG and fMRI connectomes is reproducible across simultaneous EEG-fMRI studies from 1.5T to 7TNeuroImage. 2021. DOI : 10.1016/j.neuroimage.2021.117864.
 Late post‐natal neurometabolic development in healthy male rats using 1 H and 31 P Magnetic Resonance SpectroscopyJournal of Neurochemistry. 2021. DOI : 10.1111/jnc.15294.
 Excitatory/inhibitory neuronal metabolic balance in mouse hippocampus upon infusion of [U-C-13(6)]glucoseJournal Of Cerebral Blood Flow And Metabolism. 2021. DOI : 10.1177/0271678X20910535.
 Brain NAD Is Associated With ATP Energy Production and Membrane Phospholipid Turnover in HumansFrontiers In Aging Neuroscience. 2020-12-16. DOI : 10.3389/fnagi.2020.609517.
 Contribution of macromolecules to brain H-1 MR spectra: Experts' consensus recommendationsNmr In Biomedicine. 2020-11-25. DOI : 10.1002/nbm.4393.
 Magnetic resonance spectroscopy in the rodent brain: Experts' consensus recommendationsNmr In Biomedicine. 2020-08-26. DOI : 10.1002/nbm.4325.
 C-13 Dynamic Nuclear Polarization using SA-BDPA at 6.7 T and 1.1 K: Coexistence of Pure Thermal Mixing and Well-Resolved Solid EffectJournal Of Physical Chemistry Letters. 2020-08-20. DOI : 10.1021/acs.jpclett.0c01473.
 B(0)shimming for in vivo magnetic resonance spectroscopy: Experts' consensus recommendationsNmr In Biomedicine. 2020-06-28. DOI : 10.1002/nbm.4350.
 Combined deletion of Glut1 and Glut3 impairs lung adenocarcinoma growthElife. 2020-06-23. DOI : 10.7554/eLife.53618.
 Metabolic and perfusion responses to acute hypoglycemia in the rat cortex: A non-invasive magnetic resonance approachJournal Of Neurochemistry. 2020-05-05. DOI : 10.1111/jnc.15028.
 The Appearance of the Warburg Effect in the Developing Avian Eye Characterized In Ovo: How Neurogenesis Can Remodel NeuroenergeticsInvestigative Ophthalmology & Visual Science. 2020-05-01. DOI : 10.1167/iovs.61.5.3.
 In vivo detection of d-amino acid oxidase with hyperpolarized d-[1-C-13]alanineNmr In Biomedicine. 2020-04-23. DOI : 10.1002/nbm.4303.
 Impact of aerobic exercise type on blood flow, muscle energy metabolism, and mitochondrial biogenesis in experimental lower extremity artery diseaseScientific Reports. 2020. DOI : 10.1038/s41598-020-70961-8.
 Glutamine-to-glutamate ratio in the nucleus accumbens predicts effort-based motivated performance in humansNeuropsychopharmacology. 2020. DOI : 10.1038/s41386-020-0760-6.
 Metabolic signature in nucleus accumbens for anti-depressant-like effects of acetyl-L-carnitineeLife. 2020. DOI : 10.7554/eLife.50631.
 Glucose transporter 2 mediates the hypoglycemia-induced increase in cerebral blood flowJournal Of Cerebral Blood Flow And Metabolism. 2019-09-01. DOI : 10.1177/0271678X18766743.
 N-Acetyl-Cysteine Supplementation Improves Functional Connectivity Within the Cingulate Cortex in Early Psychosis: A Pilot StudyInternational Journal of Neuropsychopharmacology. 2019-08-01. DOI : 10.1093/ijnp/pyz022.
 Evolution of the neurochemical profiles in the G93A-SOD1 mouse model of amyotrophic lateral sclerosisJournal of Cerebral Blood Flow and Metabolism. 2019-07-01. DOI : 10.1177/0271678X18756499.
 Improved off‐resonance phase behavior using a phase‐inverted adiabatic half‐passage pulse for 13 C MRS in humans at 7 TNMR in Biomedicine. 2019. DOI : 10.1002/nbm.4171.
 Multi-slice passband bSSFP for human and rodent fMRI at ultra-high fieldJournal of Magnetic Resonance. 2019. DOI : 10.1016/j.jmr.2019.05.010.
 A combined 32‐channel receive‐loops/8‐channel transmit‐dipoles coil array for whole‐brain MR imaging at 7TMagnetic Resonance in Medicine. 2019. DOI : 10.1002/mrm.27808.
 Methodological consensus on clinical proton MRS of the brain: Review and recommendationsMagnetic Resonance in Medicine. 2019. DOI : 10.1002/mrm.27742.
 Capturing the spatiotemporal dynamics of self-generated, task-initiated thoughts with EEG and fMRINeuroImage. 2019. DOI : 10.1016/j.neuroimage.2019.03.029.
 Metabolite concentration changes associated with positive and negative BOLD responses in the human visual cortex: A functional MRS study at 7 TeslaJournal of Cerebral Blood Flow & Metabolism. 2019. DOI : 10.1177/0271678X19831022.
 Investigating the variability of cardiac pulse artifacts across heartbeats in simultaneous EEG-fMRI recordings: A 7T studyNeuroImage. 2019. DOI : 10.1016/j.neuroimage.2019.02.021.
 Nucleus accumbens neurochemistry in human anxiety: A 7 T 1H-MRS studyEur Neuropsychopharmacol. 2019. DOI : 10.1016/j.euroneuro.2018.12.015.
 Impact of Caffeine Consumption on Type 2 Diabetes-Induced Spatial Memory Impairment and Neurochemical Alterations in the HippocampusFrontiers in Neuroscience. 2019. DOI : 10.3389/fnins.2018.01015.
 High-fat diet consumption alters energy metabolism in the mouse hypothalamusInternational Journal of Obesity. 2019. DOI : 10.1038/s41366-018-0224-9.
 A human cerebral and cerebellar 8-channel transceive RF dipole coil array at 7TMagnetic Resonance in Medicine. 2019. DOI : 10.1002/mrm.27476.
 Alterations of Brain Energy Metabolism in Type 2 Diabetic Goto-Kakizaki Rats Measured In Vivo by (13)C Magnetic Resonance SpectroscopyNeurotoxicity research. 2019. DOI : 10.1007/s12640-017-9821-y.
 N-acetylcysteine in a Double-Blind Randomized Placebo-Controlled Trial: Toward Biomarker-Guided Treatment in Early PsychosisSCHIZOPHRENIA BULLETIN. 2018. DOI : 10.1093/schbul/sbx093.
 N-acetylcysteine add-on treatment leads to an improvement of fornix white matter integrity in early psychosis: a double-blind randomized placebo-controlled trialTranslational Psychiatry. 2018. DOI : 10.1038/s41398-018-0266-8.
 Nutritional Ketosis Increases NAD /NADH Ratio in Healthy Human Brain: An in Vivo Study by 31P-MRSFrontiers in Nutrition. 2018. DOI : 10.3389/fnut.2018.00062.
 In vivo characterization of brain metabolism by 1 H MRS, 13 C MRS and 18 FDG PET reveals significant glucose oxidation of invasively growing glioma cellsInternational Journal of Cancer. 2018. DOI : 10.1002/ijc.31299.
 Increased hepatic fatty acid polyunsaturation precedes ectopic lipid deposition in the liver in adaptation to high-fat diets in miceMagnetic Resonance Materials in Physics, Biology and Medicine. 2018. DOI : 10.1007/s10334-017-0654-8.
 Mapping and characterization of positive and negative BOLD responses to visual stimulation in multiple brain regions at 7THuman Brain Mapping. 2018. DOI : 10.1002/hbm.24012.
 Feasibility of in vivo measurement of glucose metabolism in the mouse hypothalamus by (1) H-[(13) C] MRS at 14.1TMagnetic Resonance in Medicine. 2018. DOI : 10.1002/mrm.27129.
 Probing cardiac metabolism by hyperpolarized 13C MR using an exclusively endogenous substrate mixture and photo-induced nonpersistent radicalsMagnetic Resonance in Medicine. 2018. DOI : 10.1002/mrm.27122.
 Clinical Neuroimaging Using 7 T MRI: Challenges and ProspectsJournal of neuroimaging : official journal of the American Society of Neuroimaging. 2018. DOI : 10.1111/jon.12481.
 Astrocytic and neuronal oxidative metabolism are coupled to the rate of glutamate-glutamine cycle in the tree shrew visual cortexGlia. 2018. DOI : 10.1002/glia.23259.
 Cannabis use in early psychosis is associated with reduced glutamate levels in the prefrontal cortexPsychopharmacology. 2018. DOI : 10.1007/s00213-017-4745-z.
 In vivo (13)C MRS in the mouse brain at 14.1 Tesla and metabolic flux quantification under infusion of [1,6-(13)C2]glucoseJournal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2018. DOI : 10.1177/0271678X17734101.
 Diffusion-weighted MRS of acetate in the rat brainNMR in biomedicine. 2017. DOI : 10.1002/nbm.3768.
 Influence of physiological noise on accelerated 2D and 3D resting state functional MRI data at 7 TMagnetic resonance in medicine. 2017. DOI : 10.1002/mrm.26823.
 Social isolation stress and chronic glutathione deficiency have a common effect on the glutamine-to-glutamate ratio and myo-inositol concentration in the mouse frontal cortexJournal of neurochemistry. 2017. DOI : 10.1111/jnc.14116.
 Sexual dimorphism in hepatic lipids is associated with the evolution of metabolic status in miceNMR in biomedicine. 2017. DOI : 10.1002/nbm.3761.
 Hierarchical status predicts behavioral vulnerability and nucleus accumbens metabolic profile following chronic social defeat stress.Curr Biol. 2017. DOI : 10.1016/j.cub.2017.06.027.
 How Energy Metabolism Supports Cerebral Function: Insights from 13C Magnetic Resonance Studies In vivoFrontiers in Neuroscience. 2017. DOI : 10.3389/fnins.2017.00288.
 Energy metabolism in the rat cortex under thiopental anaesthesia measuredJournal of Neuroscience Research. 2017. DOI : 10.1002/jnr.24032.
 Progress towards in vivo brain (13)C-MRS in mice: Metabolic flux analysis in small tissue volumesAnalytical biochemistry. 2017. DOI : 10.1016/j.ab.2017.01.019.
 Glycogen Supercompensation in the Rat Brain After Acute Hypoglycemia is Independent of Glucose Levels During RecoveryNeurochemical research. 2017. DOI : 10.1007/s11064-017-2178-z.
 Technical and experimental features of Magnetic Resonance Spectroscopy of brain glycogen metabolismAnalytical Biochemistry. 2017. DOI : 10.1016/j.ab.2016.12.023.
 Studying cyto and myeloarchitecture of the human cortex at ultra-high field with quantitative imaging: R1, R⁎2 and susceptibilityNeuroImage. 2017. DOI : 10.1016/j.neuroimage.2016.12.009.
 Prospective head motion correction using FID-guided on-demand image navigatorsMagnetic resonance in medicine. 2017. DOI : 10.1002/mrm.26364.
 Early detection of human glioma sphere xenografts in mouse brain using diffusion MRI at 14.1 TNMR in Biomedicine. 2016. DOI : 10.1002/nbm.3610.
 Refined Analysis of Brain Energy Metabolism Using In Vivo Dynamic Enrichment of 13C MultipletsASN neuro. 2016. DOI : 10.1177/1759091416632342.
 Genetic Polymorphism Associated Prefrontal Glutathione and Its Coupling With Brain Glutamate and Peripheral Redox Status in Early PsychosisSchizophrenia bulletin. 2016. DOI : 10.1093/schbul/sbw038.
 3D T 2-weighted imaging at 7T using dynamic kT-points on single-transmit MRI systemsMagma (New York, N.Y.). 2016. DOI : 10.1007/s10334-016-0545-4.
 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 TJournal of Cerebral Blood Flow & Metabolism. 2016. DOI : 10.1177/0271678X16629482.
 Simultaneous and interleaved acquisition of NMR signals from different nuclei with a clinical MRI scannerMagnetic resonance in medicine. 2016. DOI : 10.1002/mrm.26056.
 Glutathione deficit affects the integrity and function of the fimbria/fornix and anterior commissure in mice: relevance for schizophreniaThe international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP). 2016. DOI : 10.1093/ijnp/pyv110.
 Hyperpolarized 6Li as a probe for hemoglobin oxygenation levelContrast Media and Molecular Imaging. 2016. DOI : 10.1002/cmmi.1656.
 Three-dimensional echo planar imaging with controlled aliasing: A sequence for high temporal resolution functional MRIMagnetic Resonance in Medicine. 2016. DOI : 10.1002/mrm.25835.
 Retrospective correction of involuntary microscopic head movement using highly accelerated fat image navigators (3D FatNavs) at 7TMagnetic Resonance in Medicine. 2016. DOI : 10.1002/mrm.25670.
 Quantitative activity-induced manganese-dependent MRI for characterizing cortical layers in the primary somatosensory cortex of the ratBrain Structure and Function. 2016. DOI : 10.1007/s00429-014-0933-3.
 GDH-Dependent Glutamate Oxidation in the Brain Dictates Peripheral Energy Substrate DistributionCell Reports. 2015. DOI : 10.1016/j.celrep.2015.09.003.
 Correcting surface coil excitation inhomogeneities in single-shot SPEN MRIJournal of Magnetic Resonance. 2015. DOI : 10.1016/j.jmr.2015.08.018.
 In Vivo Longitudinal (1)H MRS Study of Transgenic Mouse Models of Prion Disease in the Hippocampus and Cerebellum at 14.1 TNeurochemical research. 2015. DOI : 10.1007/s11064-015-1643-9.
 Stroking or Buzzing? A Comparison of Somatosensory Touch Stimuli Using 7 Tesla fMRIPloS One. 2015. DOI : 10.1371/journal.pone.0134610.
 Direct noninvasive estimation of myocardial tricarboxylic acid cycle flux in vivo using hyperpolarized 13C magnetic resonanceJournal of Molecular and Cellular Cardiology. 2015. DOI : 10.1016/j.yjmcc.2015.08.012.
 Towards high-quality simultaneous EEG-fMRI at 7T: Detection and reduction of EEG artifacts due to head motionNeuroImage. 2015. DOI : 10.1016/j.neuroimage.2015.07.020.
 Characterization of hepatic fatty acids in mice with reduced liver fat by ultra-short echo time (1) H-MRS at 14.1 T in vivoNMR in biomedicine. 2015. DOI : 10.1002/nbm.3345.
 Physiological noise in human cerebellar fMRIMagnetic Resonance Materials in Physics, Biology and Medicine. 2015. DOI : 10.1007/s10334-015-0483-6.
 Distinct contributions of Brodmann areas 1 and 2 to body ownershipSocial Cognitive and Affective Neuroscience. 2015. DOI : 10.1093/scan/nsv031.
 Imaging of prolonged BOLD response in the somatosensory cortex of the ratNMR in biomedicine. 2015. DOI : 10.1002/nbm.3263.
 Assessment of metabolic fluxes in the mouse brain in vivo using (1)H-[(13)C] NMR spectroscopy at 14.1 TeslaJournal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2015. DOI : 10.1038/jcbfm.2014.251.
 Brain energy metabolism measured by 13C magnetic resonance spectroscopy in vivo upon infusion of [3-13C]lactateJournal of Neuroscience Research. 2015. DOI : 10.1002/jnr.23531.
 A Modulated Closed Form solution for Quantitative Susceptibility Mapping - A thorough evaluation and comparison to iterative methods based on edge prior knowledgeNeuroImage. 2015. DOI : 10.1016/j.neuroimage.2014.11.038.
 Simultaneous EEG–fMRI at ultra-high field: Artifact prevention and safety assessmentNeuroImage. 2015. DOI : 10.1016/j.neuroimage.2014.10.055.
 Single acquisition electrical property mapping based on relative coil sensitivities: A proof-of-concept demonstrationMagnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. 2015. DOI : 10.1002/mrm.25399.
 Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patientsMolecular Psychiatry. 2015. DOI : 10.1038/mp.2014.88.
 Parallel imaging with phase scramblingMagnetic Resonance in Medicine. 2015. DOI : 10.1002/mrm.25252.
 Fast low-specific absorption rate B0-mapping along projections at high field using two-dimensional radiofrequency pulsesMagnetic Resonance in Medicine. 2015. DOI : 10.1002/mrm.25217.
 A double-quadrature radiofrequency coil design for proton-decoupled carbon-13 magnetic resonance spectroscopy in humans at 7TMagnetic Resonance in Medicine. 2015. DOI : 10.1002/mrm.25171.
 Non-invasive diagnostic biomarkers for estimating the onset time of permanent cerebral ischemiaJournal of Cerebral Blood Flow & Metabolism. 2014. DOI : 10.1038/jcbfm.2014.155.
 Optimized MEGA-SPECIAL for in vivo glutamine detection in the rat brain at 14.1 TNMR in Biomedicine. 2014. DOI : 10.1002/nbm.3168.
 Longitudinal neurochemical modifications in the aging mouse brain measured in vivo by 1H magnetic resonance spectroscopyNeurobiology of aging. 2014. DOI : 10.1016/j.neurobiolaging.2014.01.135.
 Image-Derived Input Function from the Vena Cava for 18F-FDG PET Studies in Rats and MiceJournal of nuclear medicine : official publication, Society of Nuclear Medicine. 2014. DOI : 10.2967/jnumed.113.127381.
 Multi-modal assessment of long-term erythropoietin treatment after neonatal hypoxic-ischemic injury in rat brainPloS One. 2014. DOI : 10.1371/journal.pone.0095643.
 Experimental peripheral arterial disease: new insights into muscle glucose uptake, macrophage, and T-cell polarization during early and late stagesPhysiological Reports. 2014. DOI : 10.1002/phy2.234.
 Clinical Proton MR Spectroscopy in Central Nervous System DisordersRadiology. 2014. DOI : 10.1148/radiol.13130531.
 Are glutamate and lactate increases ubiquitous to physiological activation? A 1H functional MR spectroscopy study during motor activation in human brain at 7TeslaNeuroImage. 2014. DOI : 10.1016/j.neuroimage.2014.02.016.
 In vivo brain macromolecule signals in healthy and glioblastoma mouse models: 1H magnetic resonance spectroscopy, post-processing and metabolite quantification at 14.1 TJournal of Neurochemistry. 2014. DOI : 10.1111/jnc.12673.
 Definition and quantification of acute inflammatory white matter injury in the immature brain by MRI/MRS at high magnetic fieldPediatric Research. 2014. DOI : 10.1038/pr.2013.242.
 Protective effects of maternal nutritional supplementation with lactoferrin on growth and brain metabolismPediatric Research. 2014. DOI : 10.1038/pr.2013.199.
 Hyperpolarized 13C lactate as a substrate for in vivo metabolic studies in skeletal muscleMetabolomics. 2014. DOI : 10.1007/s11306-014-0630-5.
 MRS glucose mapping and PET joining forces: Re-evaluation of the lumped constant in the rat brain under isoflurane anaesthesiaJournal of neurochemistry. 2014. DOI : 10.1111/jnc.12667.
 Phase-based manganese enhanced MRI, a new methodology to enhance brain cytoarchitectural contrast and study manganese uptakeMagnetic Resonance in Medicine. 2014. DOI : 10.1002/mrm.25037.
 Is the macromolecule signal tissue-specific in healthy human brain? A 1H MRS study at 7 tesla in the occipital lobeMagnetic Resonance in Medicine. 2014. DOI : 10.1002/mrm.24995.
 Improved temporal resolution for functional studies with reduced number of segments with three-dimensional echo planar imagingMagnetic Resonance in Medicine. 2014. DOI : 10.1002/mrm.24975.
 In vivo quantification of neuro-glial metabolism and glial glutamate concentration using 1H-[13C] MRS at 14.1TJournal of Neurochemistry. 2014. DOI : 10.1111/jnc.12479.
 An improved trap design for decoupling multinuclear RF coilsMagnetic Resonance in Medicine. 2014. DOI : 10.1002/mrm.24931.
 Improving T2 -weighted imaging at high field through the use of kT -pointsMagnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. 2014. DOI : 10.1002/mrm.24805.
 Human finger somatotopy in areas 3b, 1, and 2: A 7T fMRI study using a natural stimulusHuman brain mapping. 2014. DOI : 10.1002/hbm.22172.
 Metabolic Flux and Compartmentation Analysis in the Brain In vivoFrontiers in Endocrinology. 2013. DOI : 10.3389/fendo.2013.00156.
 Direct mapping of 19F in 19FDG-6P in brain tissue at subcellular resolution using soft X-ray fluorescenceJournal of Physics: Conference Series. 2013. DOI : 10.1088/1742-6596/463/1/012003.
 Brain Glucose Transport and Phosphorylation Under Acute Insulin-Induced Hypoglycemia in Mice: An 18F-FDG PET StudyJournal of Nuclear Medicine. 2013. DOI : 10.2967/jnumed.113.122812.
 The C57BL/6J Mouse Exhibits Sporadic Congenital Portosystemic ShuntsPLoS ONE. 2013. DOI : 10.1371/journal.pone.0069782.
 New Developments and Applications of the MP2RAGE Sequence - Focusing the Contrast and High Spatial Resolution R1 MappingPloS One. 2013. DOI : 10.1371/journal.pone.0069294.
 Glutamatergic and GABAergic energy metabolism measured in the rat brain by 13C NMR spectroscopy at 14.1 TJournal of Neurochemistry. 2013. DOI : 10.1111/jnc.12333.
 Unedited in vivo detection and quantification of gamma-aminobutyric acid in the occipital cortex using short-TE MRS at 3 TNMR in Biomedicine. 2013. DOI : 10.1002/nbm.2960.
 3D Residual Eddy Current Field Characterisation: applied to Diffusion Weighted Magnetic Resonance ImagingIEEE Transactions on Medical Imaging. 2013. DOI : 10.1109/TMI.2013.2259249.
 Single spin-echo T 2 relaxation times of cerebral metabolites at 14.1 T in the in vivo rat brainMagma (New York, N.Y.). 2013. DOI : 10.1007/s10334-013-0378-3.
 Hepatic glucose sensing is required to preserve β cell glucose competenceThe Journal of clinical investigation. 2013. DOI : 10.1172/JCI65538.
 In vivo enzymatic activity of acetylCoA synthetase in skeletal muscle revealed by (13)C turnover from hyperpolarized [1-(13)C]acetate to [1-(13)C]acetylcarnitineBiochimica et biophysica acta. 2013. DOI : 10.1016/j.bbagen.2013.03.023.
 Investigation of field and diffusion time dependence of the diffusion-weighted signal at ultrahigh magnetic fieldsNMR in biomedicine. 2013. DOI : 10.1002/nbm.2945.
 9.4-14.1 T small-animal PET-MR imaging: Feasibility analysis of LYSO APD readout via long signal linesNuclear Instruments & Methods In Physics Research Section A-Accelerators Spectrometers Detectors And Associated Equipment. 2013. DOI : 10.1016/j.nima.2012.08.032.
 Feasibility and electromagnetic compatibility study of the ClearPEM front-end electronics for simultaneous PET-MR imagingNuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment. 2013. DOI : 10.1016/j.nima.2012.08.033.
 Characterization of sustained BOLD activation in the rat barrel cortex and Neurochemical consequencesNeuroimage. 2013. DOI : 10.1016/j.neuroimage.2013.02.042.
 Quantification of the neurochemical profile using simulated macromolecule resonances at 3 TNMR in biomedicine. 2013. DOI : 10.1002/nbm.2896.
 Net increase of lactate and glutamate concentration in activated human visual cortex detected with magnetic resonance spectroscopy at 7 teslaJournal of neuroscience research. 2013. DOI : 10.1002/jnr.23194.
 Feasibility of direct mapping of cerebral fluorodeoxy-D-glucose metabolism in situ at subcellular resolution using soft X-ray fluorescenceJournal of neuroscience research. 2013. DOI : 10.1002/jnr.23171.
 Digit somatotopy in the human cerebellum: A 7T fMRI studyNeuroImage. 2013. DOI : 10.1016/j.neuroimage.2012.11.041.
 Proton T(1) relaxation times of metabolites in human occipital white and gray matter at 7 TMagnetic Resonance in Medicine. 2013. DOI : 10.1002/mrm.24352.
 An in vivo ultrahigh field 14.1 T (1) H-MRS study on 6-OHDA and α-synuclein-based rat models of Parkinson's disease: GABA as an early disease markerNMR in biomedicine. 2013. DOI : 10.1002/nbm.2817.
 Which prior knowledge? Quantification of in vivo brain (13) C MR spectra following (13) C glucose infusion using AMARESMagnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. 2013. DOI : 10.1002/mrm.24406.
Radical-free hyperpolarized MRI using endogenously occurring pyruvate analogues and UV-induced nonpersistent radicals
It was recently demonstrated that nonpersistent radicals can be generated in frozen solutions of metabolites such as pyruvate by irradiation with UV light, enabling radical-free dissolution dynamic nuclear polarization. Although pyruvate is endogenous, the presence of pyruvate may interfere with metabolic processes or the detection of pyruvate as a metabolic product, making it potentially unsuitable as a polarizing agent. Therefore, the aim of the current study was to characterize solutions containing endogenously occurring alternatives to pyruvate as UV-induced nonpersistent radical precursors for in vivo hyperpolarized MRI. The metabolites alpha-ketovalerate (alpha kV) and alpha-ketobutyrate (alpha kB) are analogues of pyruvate and were chosen as potential radical precursors. Sample formulations containing alpha kV and alpha kB were studied with UV-visible spectroscopy, irradiated with UV light, and their nonpersistent radical yields were quantified with electron spin resonance and compared with pyruvate. The addition of C-13-labeled substrates to the sample matrix altered the radical yield of the precursors. Using alpha kB increased the C-13-labeled glucose liquid-state polarization to 16.3% /- 1.3% compared with 13.3% /- 1.5% obtained with pyruvate, and 8.9% /- 2.1% with alpha kV. For [1-C-13]butyric acid, polarization levels of 12.1% /- 1.1% for alpha kV, 12.9% /- 1.7% for alpha kB, 1.5% /- 0.2% for OX063 and 18.7% /- 0.7% for Finland trityl, were achieved. Hyperpolarized [1-C-13]butyrate metabolism in the heart revealed label incorporation into [1-C-13]acetylcarnitine, [1-C-13]acetoacetate, [1-C-13]butyrylcarnitine, [5-C-13]glutamate and [5-C-13]citrate. This study demonstrates the potential of alpha kV and alpha kB as endogenous polarizing agents for in vivo radical-free hyperpolarized MRI. UV-induced, nonpersistent radicals generated in endogenous metabolites enable high polarization without requiring radical filtration, thus simplifying the quality-control tests in clinical applications.
Nmr In Biomedicine
DOI : 10.1002/nbm.4584
Measuring Glycolytic Activity with Hyperpolarized [2H7, U-13C6] D-Glucose in the Naive Mouse Brain under Different Anesthetic Conditions
Glucose is the primary fuel for the brain; its metabolism is linked with cerebral function. Different magnetic resonance spectroscopy (MRS) techniques are available to assess glucose metabolism, providing complementary information. Our first aim was to investigate the difference between hyperpolarized 13C-glucose MRS and non-hyperpolarized 2H-glucose MRS to interrogate cerebral glycolysis. Isoflurane anesthesia is commonly employed in preclinical MRS, but it affects cerebral hemodynamics and functional connectivity. A combination of low doses of isoflurane and medetomidine is routinely used in rodent fMRI and shows similar functional connectivity, as in awake animals. As glucose metabolism is tightly linked to neuronal activity, our second aim was to assess the impact of these two anesthetic conditions on the cerebral metabolism of glucose. Brain metabolism of hyperpolarized 13C-glucose and 2H-glucose was monitored in two groups of mice in a 9.4 T MRI system. We found that the very different duration and temporal resolution of the two techniques enable highlighting the different aspects in glucose metabolism. We demonstrate (by numerical simulations) that hyperpolarized 13C-glucose reports on de novo lactate synthesis and is sensitive to CMRGlc. We show that variations in cerebral glucose metabolism, under different anesthesia, are reflected differently in hyperpolarized and non-hyperpolarized X-nuclei glucose MRS.
DOI : 10.3390/metabo11070413
Dipole-Fed Rectangular Dielectric Resonator Antennas for Magnetic Resonance Imaging at 7 T: The Impact of Quasi-Transverse Electric Modes on Transmit Field Distribution
Shortened dipole antennas based on rectangular dielectric blocks play an important role in ultrahigh field magnetic resonance imaging (UHF-MRI) radio frequency (RF) coil design. However, the generally assumed direct contact with the subject is difficult to maintain in typical in vivo settings. We have previously observed that certain dielectrically shortened dipole antennas can produce a substantially altered transmit field distribution with a very low transmit efficiency when the block and the sample are physically separated. Therefore, the aim of this study was to determine a) why certain designs of dielectrically shortened dipole antennas can produce an inefficient transmit field when the block and the sample are physically separated and b) how this depends on key parameters such as rectangular block geometry, dielectric constant, loading geometry, and RF feeding. In this work, two main types of quasi-transverse dielectric modes were found in different rectangular block geometries and interpreted as TE11 delta z (MR efficient) and TE1 delta delta y (MR inefficient), and their impact on in vivo MRI experiments involving the human head, calf, and wrist was explored. This study shows, for the first time, why certain antennas preserve their transmit field efficiency despite physical separation from the sample. We conclude that the proposed approach has the potential to provide new insights into dipole antenna design for UHF-MRI.
Frontiers In Physics
DOI : 10.3389/fphy.2021.675509
Redox Dysregulation, Myelination Deficit and Dysconnectivity in Schizophrenia: A Translational Study in First Episode Patients and Experimental Models2021-05-01. p. S56-S56.
PIRACY: An Optimized Pipeline for Functional Connectivity Analysis in the Rat Brain
Resting state functional MRI (rs-fMRI) is a widespread and powerful tool for investigating functional connectivity (FC) and brain disorders. However, FC analysis can be seriously affected by random and structured noise from non-neural sources, such as physiology. Thus, it is essential to first reduce thermal noise and then correctly identify and remove non-neural artifacts from rs-fMRI signals through optimized data processing methods. However, existing tools that correct for these effects have been developed for human brain and are not readily transposable to rat data. Therefore, the aim of the present study was to establish a data processing pipeline that can robustly remove random and structured noise from rat rs-fMRI data. It includes a novel denoising approach based on the Marchenko-Pastur Principal Component Analysis (MP-PCA) method, FMRIB's ICA-based Xnoiseifier (FIX) for automatic artifact classification and cleaning, and global signal regression (GSR). Our results show that: (I) MP-PCA denoising substantially improves the temporal signal-to-noise ratio, (II) the pre-trained FIX classifier achieves a high accuracy in artifact classification, and (III) both independent component analysis (ICA) cleaning and GSR are essential steps in correcting for possible artifacts and minimizing the within-group variability in control animals while maintaining typical connectivity patterns. Reduced within-group variability also facilitates the exploration of potential between-group FC changes, as illustrated here in a rat model of sporadic Alzheimer's disease.
Frontiers In Neuroscience
DOI : 10.3389/fnins.2021.602170
Hyperpolarized C-13-glucose magnetic resonance highlights reduced aerobic glycolysis in vivo in infiltrative glioblastoma
Glioblastoma (GBM) is the most aggressive brain tumor type in adults. GBM is heterogeneous, with a compact core lesion surrounded by an invasive tumor front. This front is highly relevant for tumor recurrence but is generally non-detectable using standard imaging techniques. Recent studies demonstrated distinct metabolic profiles of the invasive phenotype in GBM. Magnetic resonance (MR) of hyperpolarized C-13-labeled probes is a rapidly advancing field that provides real-time metabolic information. Here, we applied hyperpolarized C-13-glucose MR to mouse GBM models. Compared to controls, the amount of lactate produced from hyperpolarized glucose was higher in the compact GBM model, consistent with the accepted "Warburg effect". However, the opposite response was observed in models reflecting the invasive zone, with less lactate produced than in controls, implying a reduction in aerobic glycolysis. These striking differences could be used to map the metabolic heterogeneity in GBM and to visualize the infiltrative front of GBM.
DOI : 10.1038/s41598-021-85339-7
Development and applications of hyperpolarized 13C and 1H MR spectroscopy of cerebral metabolism at ultra-high field
This thesis is composed of four studies centered on investigating cerebral metabolism using magnetic resonance spectroscopy (MRS) of hyperpolarized and non-hyperpolarized compounds at ultra-high field. In the first two chapters, we studied longitudinally the effects of different treatments for hepatic encephalopathy (HE) on the neurometabolic changes associated with chronic HE using a rat model of type C HE and a multimodal approach including 1H MRS. The effects of the antibiotic rifaximin administered at different doses as well as its combination with probiotics were studied in the established model of bile duct ligated (BDL) rats. We showed for the first time the beneficial effects of the combined rifaximin and the probiotic Vivomixx® on the neurometabolic changes in vivo and longitudinally in a rat model of type C HE. The longitudinal changes of some brain metabolites concentration (glutamine, glutamate, creatine), as well as gut bifidobacteria concentration, were significantly less pronounced in the group of rats treated with rifaximin and probiotics compared to non-treated rats. We also showed that rifaximin treatment alone had limited efficacy. When administered at human dose in rats, its effects appeared only at the early stages of the disease, whereas at a higher dose some neurometabolic changes associated with HE were attenuated but the general condition of the rats was worse. In the third study, we used dissolution dynamic nuclear polarization (DNP) to hyperpolarize [2H7, U-13C6]-D-glucose, which enabled us to monitor real-time glycolysis in the healthy mouse brain. Given that glucose metabolism is tightly linked to neuronal activity, we first investigated how the change in anesthesia impacts the cerebral metabolism of hyperpolarized glucose. Anesthetics are known to influence brain activity, and in this study we showed for the first time that switching from isoflurane anesthesia to a combination of lower doses of isoflurane and medetomidine had a high impact on cerebral glucose uptake and glycolytic flow, as reflected by the increased labelling of downstream [1-13C] lactate. The second part of this study aimed at evaluating the feasibility of quantifying cerebral glucose metabolism kinetics by evaluating two different mathematical models, where kinetic rate constants were determined by fitting the models on 13C curves by non-linear regression using the Levenberg-Marquardt algorithm. We showed that a 3-compartment model is more stable and reliable than a 4-compartment model. Finally, since lithium salts are widely used for treating bipolar disorder but its mechanism of action is still not clearly understood, we evaluated the potential of hyperpolarized 6Li injected at pharmacological doses to assess its real-time bio-distribution and pharmacokinetic in the rat brain. We demonstrated first that hyperpolarized 6Li can be detected at pharmacological concentration in the rat head with high signal-to-noise ratio (SNR). We also showed that the transport of lithium through the intact blood-brain barrier brain is a limiting factor and demonstrated a striking difference between apparent 6Li T1 values in a brain with normal or disrupted blood-brain barrier.Lausanne, EPFL, 2021.
DOI : 10.5075/epfl-thesis-7818.
Mechanistic studies of DNP and applications of hyperpolarized probes to study renal physiology and metabolism
Dissolution dynamic nuclear polarization (dDNP) is a powerful technique that enhances the magnetic resonance signal of nuclear spins by several orders of magnitude. DNP relies on the principle of cross-relaxation by electron spins driven out of equilibrium to enhance nuclear polarization. When coupled to magnetic resonance spectroscopy/imaging (MRS/I), infusion of 13C-labeled tracers hyperpolarized via DNP in vivo provides real-time estimates of metabolic fluxes, physiological parameters and/or tissue perfusion. The present work focuses on fundamental aspects of DNP, in particular how sample composition affects the DNP of low-gamma nuclei, as well as on in vivo dDNP applications targeting renal metabolism and physiology. The DNP properties of the SA-BDPA radical were studied in a sample of 13C-urea. SA-BDPA, a water-soluble derivative of BDPA, is characterized by a small g-anisotropy and unresolved hyperfine coupling to protons. As a result, at 6.7 T, 1.1 K its ESR linewidth is much smaller than the 13C Larmor frequency, which enabled the observation for the first time of 13C DNP via the solid effect and pure thermal mixing, the latter defined as the process where the electron non-Zeeman reservoir alone provides the energy required for triple-spin flips. The effect of solvent deuteration on 6Li DNP and radical ESR properties was studied in 6LiCl water:glycerol solutions doped with either the nitroxide radical TEMPOL or the trityl radical OX063. Unexpectedly, the TEMPOL-doped samples polarized better than the trityl-doped ones. Across all samples, the relationship between the degree of solvent deuteration with the buildup time constant and polarization level was notably different from what has been reported for 13C. This behavior is indicative of DNP via a combination of the cross effect and thermal mixing mechanisms. The uptake and metabolism of hyperpolarized L-[1-13C]alaninamide was investigated in the rat kidney in vivo. This probe of aminopeptidase N, which can play a role in tumor growth, was previously studied in vitro. Our study showed that alanine production from alaninamide also occurs in vivo, however, with spectral overlap of substrate and product. Alaninamide, having a pKa of 7.9, proved to be sensitive to local pH. Three spectral peaks, corresponding to at least three environments with different pH values, could be observed in the kidney. The two peaks at higher pH were assigned to the blood extra- and (partially) intracellular compartments, while the third one was mainly in the inner part of the kidney. Finally, alaninamide was shown to also be sensitive to dissolved CO2, with the rapid formation of a carbamate adduct following infusion. The renal metabolism of D-[1-13C]alanine by D-amino acid oxidase (DAO) was also studied. Conversion of hyperpolarized D-alanine to pyruvate and further metabolism to lactate and bicarbonate was observed in the kidney only when DAO was not inhibited. DAO activity could also be detected in blood, where leukocytes express the enzyme, but not in the brain and liver, in line with their lower DAO activity. Overall, this thesis provides additional insight into how the experimental conditions can favor a particular DNP mechanism over another. It also significantly expands the scope of in vivo dDNP applications, showing that additional enzyme-catalyzed processes can be detected, along with the potential of amino-acid based hyperpolarized 13C sensors for physiological studies.Lausanne, EPFL, 2021.
DOI : 10.5075/epfl-thesis-10666.
Methods to Enhance Nuclear Magnetic Resonance Sensitivity at High Magnetic Field
MR is a well-established technique routinely used in preclinical and clinical studies. This thesis focussed on the improvement of sensitivity of different methods in MR. Hyperpolarized 129Xe gas is used for studying pulmonary disease or cerebral perfusion. When hyperpolarization is conducted inside a polarizer, the achieved solid state polarization is currently limited to a few percent. One aim of this thesis was to counteract this bottleneck by investigating the effect of microwave frequency modulation for different spin systems. An increase in nuclear 129Xe spin polarization up to 14.5% was achieved compared to the polarization obtained without frequency modulation. Electron spin-lattice relaxation times T1S, as short as 5 ms, correlated directly with the gain in 129Xe nuclear polarization due to microwave frequency modulation, irrespective of the solvent or its deuteration. Simulations of the electron spin system confirmed that microwave frequency modulation could be an efficient method to considerably enhance nuclear spin polarization in short T1S matrices or in the presence of large linewidth radicals by promoting spectral diffusion. DNP matrices can also be hyperpolarized through non-persistent radicals generated by UV-irradiation. They have the advantage of quenching upon dissolution, yielding a hyperpolarized solution with no need for radical filtration. Radical precursors researched up to date either yielded low 13C polarization, contained toxic matrix components or interfered with metabolic processes. Therefore, the two novel endogenously-occurring precursors, alpha-ketovalerate (akV) and alpha-ketobutyrate (akB) were investigated. Liquid state polarization of the metabolic substrate glucose increased to 16.3% using akB compared with 13.3% obtained with pyruvate. [1-13C]butyric acid was polarized to 12.1% for akV and 12.9% for akB and used for in vivo hyperpolarized cardiac MRS. Hyperpolarized [1-13C]butyrate metabolism in the heart revealed label incorporation into a wide range of metabolites. This study demonstrated the potential of using UV-induced radicals generated in the endogenously-occurring metabolites akV and akB as polarizing agents, enabling high polarization without requiring radical filtration for radical-free hyperpolarized MRI. While MRI requires RF coils that generate high B1 homogeneity, MRS strongly depends on high sensitivity and potentially high B1 efficiency to allow for short-TE acquisitions. Two custom-made 1H coils resonating at 600 MHz, a single-channel saddle coil and an 8-leg quadrature birdcage coil, were investigated with respect to those criteria for applications at ultra-high field (14.1 T). The saddle coil yielded a 54% higher transmit field efficiency with a 20% higher SNR compared to the birdcage coil after full-FOV corrections. Using the saddle coil in glycoCEST imaging of a homogeneous phantom resulted in an MTR asymmetry coefficient of variation as small as 5.2% over an 11 mm diameter ROI. Overall, the saddle coil provided a good compromise between globally homogeneous excitation and high sensitivity. Finally, it was successfully used to map skeletal muscle glycogen content in vivo. This thesis focused on improving MR sensitivity by means of adequate custom-made RF coils as well as DNP through the implementation of a method capitalizing on electronic spin properties and the development of novel endogenous precursors for in vivo hyperpolarized MRI.Lausanne, EPFL, 2021.
DOI : 10.5075/epfl-thesis-8460.
The relationship between EEG and fMRI connectomes is reproducible across simultaneous EEG-fMRI studies from 1.5T to 7T
Both electroencephalography (EEG) and functional Magnetic Resonance Imaging (fMRI) are non-invasive methods that show complementary aspects of human brain activity. Despite measuring different proxies of brain activity, both the measured blood-oxygenation (fMRI) and neurophysiological recordings (EEG) are indirectly coupled. The electrophysiological and BOLD signal can map the underlying functional connectivity structure at the whole brain scale at different timescales. Previous work demonstrated a moderate but significant correlation between resting-state functional connectivity of both modalities, however there is a wide range of technical setups to measure simultaneous EEG-fMRI and the reliability of those measures between different setups remains unknown. This is true notably with respect to different magnetic field strengths (low and high field) and different spatial sampling of EEG (medium to high-density electrode coverage). Here, we investigated the reproducibility of the bimodal EEG-fMRI functional connectome in the most comprehensive resting-state simultaneous EEG-fMRI dataset compiled to date including a total of 72 subjects from four different imaging centers. Data was acquired from 1.5T, 3T and 7T scanners with simultaneously recorded EEG using 64 or 256 electrodes. We demonstrate that the whole-brain monomodal connectivity reproducibly correlates across different datasets and that a moderate crossmodal correlation between EEG and fMRI connectivity of r ≈ 0.3 can be reproducibly extracted in low- and high-field scanners. The crossmodal correlation was strongest in the EEG-β frequency band but exists across all frequency bands. Both homotopic and within intrinsic connectivity network (ICN) connections contributed the most to the crossmodal relationship. This study confirms, using a considerably diverse range of recording setups, that simultaneous EEG-fMRI offers a consistent estimate of multimodal functional connectomes in healthy subjects that are dominantly linked through a functional core of ICNs across spanning across the different timescales measured by EEG and fMRI. This opens new avenues for estimating the dynamics of brain function and provides a better understanding of interactions between EEG and fMRI measures. This observed level of reproducibility also defines a baseline for the study of alterations of this coupling in pathological conditions and their role as potential clinical markers.
DOI : 10.1016/j.neuroimage.2021.117864
Late post‐natal neurometabolic development in healthy male rats using 1 H and 31 P Magnetic Resonance Spectroscopy
Brain metabolism evolves rapidly during early post‐natal development in the rat. While changes in amino acids, energy metabolites, antioxidants or metabolites involved in phospholipid metabolism have been reported in the early stages, neurometabolic changes during the later post‐natal period are less well characterized. Therefore, we aimed to assess the neurometabolic changes in male Wistar rats between post‐natal days 29 and 77 (p29‐p77) using longitudinal magnetic resonance spectroscopy (MRS) in vivo at 9.4 Tesla. 1H MRS was performed in the hippocampus between p29‐p77 at one‐week intervals (n=7) and in the cerebellum between p35‐p77 at two‐week intervals (n=7) using the SPECIAL sequence at ultra‐short echo‐time. NOE enhanced and 1H decoupled 31P MR spectra were acquired at p35, p48 and p63 (n=7) in a larger voxel covering cortex, hippocampus and part of the striatum. The hippocampus showed a decrease in taurine concentration and an increase in glutamate (with more pronounced changes until p49), seemingly a continuation of their well described changes in the early post‐natal period. A constant increase in myo‐inositol‐ and choline‐containing compounds in the hippocampus (in particular glycero‐phosphocholine as shown by 31P MRS) was measured throughout the observation period, probably related to membrane metabolism and myelination. The cerebellum showed only a significant increase in myo‐inositol between p35‐p77. In conclusion, the present study showed important changes in brain metabolites in both the hippocampus and cerebellum in the later post‐natal period (p29/p35‐p77) of male rats, something previously unreported. Based on these novel data, changes in some neurometabolites beyond p28‐35, conventionally accepted as the cut off for adulthood, should be taken into account in both experimental design and data interpretation in this animal model.
Journal of Neurochemistry
DOI : 10.1111/jnc.15294
Excitatory/inhibitory neuronal metabolic balance in mouse hippocampus upon infusion of [U-C-13(6)]glucose
Hippocampus plays a critical role in linking brain energetics and behavior typically associated to stress exposure. In this study, we aimed to simultaneously assess excitatory and inhibitory neuronal metabolism in mouse hippocampus in vivo by applying (18)FDG-PET and indirect C-13 magnetic resonance spectroscopy (H-1-[C-13]-MRS) at 14.1 T upon infusion of uniformly C-13-labeled glucose ([U-C-13(6)]Glc). Improving the spectral fitting by taking into account variable decoupling efficiencies of [U-C-13(6)]Glc and refining the compartmentalized model by including two gamma-aminobutyric acid (GABA) pools permit us to evaluate the relative contributions of glutamatergic and GABAergic metabolism to total hippocampal neuroenergetics. We report that GABAergic activity accounts for similar to 13% of total neurotransmission (V-NT) and similar to 27% of total neuronal TCA cycle (V-TCA) in mouse hippocampus suggesting a higher V-TCA/V-NT ratio for inhibitory neurons compared to excitatory neurons. Finally, our results provide new strategies and tools for bringing forward the developments and applications of C-13-MRS in specific brain regions of small animals.
Journal Of Cerebral Blood Flow And Metabolism
DOI : 10.1177/0271678X20910535
Brain NAD Is Associated With ATP Energy Production and Membrane Phospholipid Turnover in Humans
The brain requires a large amount of energy, mostly derived from the metabolism of glucose, which decreases substantially with age and neurological diseases. While mounting evidence in model organisms illustrates the central role of brain nicotinamide adenine dinucleotide (NAD) for maintaining energy homeostasis, similar data are sparse in humans. This study explores the correlations between brain NAD, energy production and membrane phospholipid metabolism by 31-phosphorous magnetic resonance spectroscopy (P-31-MRS) across 50 healthy participants including a young (mean age 27.1-year-old) and middle-aged (mean age 56.4-year-old) group. The analysis revealed that brain NAD level and NAD( )/NADH redox ratio were positively associated with ATP level and the rate of energy production, respectively. Moreover, a metabolic network linking NAD with membrane phospholipid metabolism, energy production, and aging was identified. An inverted trend between age and NAD level was detected. These results pave the way for the use of P-31-MRS as a powerful non-invasive tool to support the development of new therapeutic interventions targeting NAD associated phospho-metabolic pathways in brain aging and neurological diseases.
Frontiers In Aging Neuroscience
DOI : 10.3389/fnagi.2020.609517
Contribution of macromolecules to brain H-1 MR spectra: Experts' consensus recommendations
Proton MR spectra of the brain, especially those measured at short and intermediate echo times, contain signals from mobile macromolecules (MM). A description of the main MM is provided in this consensus paper. These broad peaks of MM underlie the narrower peaks of metabolites and often complicate their quantification but they also may have potential importance as biomarkers in specific diseases. Thus, separation of broad MM signals from low molecular weight metabolites enables accurate determination of metabolite concentrations and is of primary interest in many studies. Other studies attempt to understand the origin of the MM spectrum, to decompose it into individual spectral regions or peaks and to use the components of the MM spectrum as markers of various physiological or pathological conditions in biomedical research or clinical practice. The aim of this consensus paper is to provide an overview and some recommendations on how to handle the MM signals in different types of studies together with a list of open issues in the field, which are all summarized at the end of the paper.
Nmr In Biomedicine
DOI : 10.1002/nbm.4393
Magnetic resonance spectroscopy in the rodent brain: Experts' consensus recommendations
In vivo MRS is a non-invasive measurement technique used not only in humans, but also in animal models using high-field magnets. MRS enables the measurement of metabolite concentrations as well as metabolic rates and their modifications in healthy animals and disease models. Such data open the way to a deeper understanding of the underlying biochemistry, related disturbances and mechanisms taking place during or prior to symptoms and tissue changes. In this work, we focus on the main preclinical(1)H,P-31 and(13)C MRS approaches to study brain metabolism in rodent models, with the aim of providing general experts' consensus recommendations (animal models, anesthesia, data acquisition protocols). An overview of the main practical differences in preclinical compared with clinical MRS studies is presented, as well as the additional biochemical information that can be obtained in animal models in terms of metabolite concentrations and metabolic flux measurements. The properties of high-field preclinical MRS and the technical limitations are also described.
Nmr In Biomedicine
DOI : 10.1002/nbm.4325
C-13 Dynamic Nuclear Polarization using SA-BDPA at 6.7 T and 1.1 K: Coexistence of Pure Thermal Mixing and Well-Resolved Solid Effect
SA-BDPA is a water-soluble, narrow-line width radical previously used for dynamic nuclear polarization (DNP) signal enhancement in solid-state magic angle spinning NMR spectroscopy. Here, we report the first study using SA-BDPA under dissolution DNP conditions (6.7 T and 1.15 K). Longitudinal-detected (LOD)-electron spin resonance (ESR) and C-13 DNP measurements were performed on samples containing 8.4 M [C-13]urea dissolved in 50:50 water:glycerol (v/v) doped with either 60 or 120 mM SA-BDPA. Two distinct DNP mechanisms, both "pure" thermal mixing and a well-resolved solid effect could clearly be identified. The radical's ESR line width (30-40 MHz), broadened predominantly by dipolar coupling, excluded any contribution from the cross effect. Microwave frequency modulation increased the enhancement by DNP at the lower radical concentration but not at the higher radical concentration. These results are compared to data acquired with trityl radical AH111501, highlighting the unusual C-13 DNP properties of SA-BDPA.
Journal Of Physical Chemistry Letters
DOI : 10.1021/acs.jpclett.0c01473
B(0)shimming for in vivo magnetic resonance spectroscopy: Experts' consensus recommendations
Magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) allow the chemical analysis of physiological processes in vivo and provide powerful tools in the life sciences and for clinical diagnostics. Excellent homogeneity of the static B(0)magnetic field over the object of interest is essential for achieving high-quality spectral results and quantitative metabolic measurements. The experimental minimization of B(0)variation is performed in a process called B(0)shimming. In this article, we summarize the concepts of B(0)field shimming using spherical harmonic shimming techniques, specific strategies for B(0)homogenization and crucial factors to consider for implementation and use in both brain and body. In addition, experts' recommendations are provided for minimum requirements for B(0)shim hardware and evaluation criteria for the primary outcome of adequate B(0)shimming for MRS and MRSI, such as the water spectroscopic linewidth.
Nmr In Biomedicine
DOI : 10.1002/nbm.4350
Combined deletion of Glut1 and Glut3 impairs lung adenocarcinoma growth
Glucose utilization increases in tumors, a metabolic process that is observed clinically by F-18-fluorodeoxyglucose positron emission tomography (F-18-FDG-PET). However, is increased glucose uptake important for tumor cells, and which transporters are implicated in vivo? In a genetically-engineered mouse model of lung adenocarcinoma, we show that the deletion of only one highly expressed glucose transporter, Glut1 or Glut3, in cancer cells does not impair tumor growth, whereas their combined loss diminishes tumor development. F-18-FDG-PET analyses of tumors demonstrate that Glut1 and Glut3 loss decreases glucose uptake, which is mainly dependent on Glut1. Using C-13-glucose tracing with correlated nanoscale secondary ion mass spectrometry (NanoSIMS) and electron microscopy, we also report the presence of lamellar body-like organelles in tumor cells accumulating glucose-derived biomass, depending partially on Glut1. Our results demonstrate the requirement for two glucose transporters in lung adenocarcinoma, the dual blockade of which could reach therapeutic responses not achieved by individual targeting.
DOI : 10.7554/eLife.53618
Metabolic and perfusion responses to acute hypoglycemia in the rat cortex: A non-invasive magnetic resonance approach
Hypoglycemia is critical condition during diabetic treatment that involves intensive insulin therapy, and it may impair brain function. We aimed to compare cortical responses of three hypoglycemic phases and the restoration of glycemia to control levels after a severe episode in rats using non-invasive perfusion magnetic resonance (MR) imaging and localized H-1 MR spectroscopy. Under light alpha-chloralose anesthesia, cortical blood flow (cCBF) was 42 /- 3 ml/100 g/min at euglycemia ( 5 mM plasma glucose), was not altered at mild hypoglycemia I (42 /- 4 ml/100 g/min, 2-3.5 mM), increased to 60 /- 8 ml/100 g/min under moderate hypoglycemia II (1-2 mM) and amplified to 190 /- 35 ml/100 g/min at severe hypoglycemia III (< 1 mM). H-1 MRS revealed metabolic changes at hypoglycemia I without any perfusion alteration. At hypoglycemia III, glutamine and glutamate decreased, whereas aspartate increased. When animals subsequently regained glycemic control, not all metabolites returned to their control levels, for example, glutamine. Meanwhile, ascorbate was increased with amplified hypoglycemic severity, whereas glutathione was reduced; these compounds did not return to normal levels upon the restoration of glycemia. Our study is the first to report cCBF and neurochemical changes in cortex upon five glycemic stages. The cortical responses of different hypoglycemic phases would explain variable neuronal damages after hypoglycemia and might help identify the degrees of hypoglycemic insults and further improve alternative therapies.
Journal Of Neurochemistry
DOI : 10.1111/jnc.15028
Redox Dysregulation, Myelination Deficit and Dysconnectivity in Schizophrenia: A Translational Study in First Episode Patients and Experimental Models2020-05-01. p. S100-S100.
DOI : 10.1016/j.biopsych.2020.02.275.
The Appearance of the Warburg Effect in the Developing Avian Eye Characterized In Ovo: How Neurogenesis Can Remodel Neuroenergetics
PURPOSE. The avian eye is an established model for exploring mechanisms that coordinate morphogenesis and metabolism during embryonic development. Less is known, however, about trafficking of bioenergetic and metabolic signaling molecules that are involved in retinal neurogenesis. METHODS. Here we tested whether the known 3-day delayed neurogenesis occurring in the pigeon compared with the chick was associated with a deferred reshaping of eye metabolism in vivo. Developmental metabolic remodeling was explored using H-1-magnetic resonance spectroscopy of the whole eye and vitreous body, in ovo, in parallel with biochemical and molecular analyses of retinal, vitreous, and lens extracts from bird embryos. RESULTS. Cross-species comparisons enabled us to show that a major glycolytic switch in the retina is related to neurogenesis rather than to eye growth. We further show that the temporal emergence of an interlocking regulatory cascade controlling retinal oxidative phosphorylation and glycolysis results in the exchange of lactate and citrate between the retina and vitreous. CONCLUSIONS. Our results point to the vitreous as a reservoir and buffer of energy metabolites that provides trophic support to oxidative neurons, such as retinal ganglion cells, in early development. Through its control of key glycolytic regulatory enzymes, citrate, exchanged between extracellular and intracellular compartments between the retina and vitreous, is a key metabolite in the initiation of a glycolytic switch.
Investigative Ophthalmology & Visual Science
DOI : 10.1167/iovs.61.5.3
In vivo detection of d-amino acid oxidase with hyperpolarized d-[1-C-13]alanine
d-amino acid oxidase (DAO) is a peroxisomal enzyme that catalyzes the oxidative deamination of several neutral and basic d-amino acids to their corresponding alpha-keto acids. In most mammalian species studied, high DAO activity is found in the kidney, liver, brain and polymorphonuclear leukocytes, and its main function is to maintain low circulating d-amino acid levels. DAO expression and activity have been associated with acute and chronic kidney diseases and with several pathologies related to N-methyl-d-aspartate (NMDA) receptor hypo/hyper-function; however, its precise role is not completely understood. In the present study we show that DAO activity can be detected in vivo in the rat kidney using hyperpolarized d-[1-C-13]alanine. Following a bolus of hyperpolarized d-alanine, accumulation of pyruvate, lactate and bicarbonate was observed only when DAO activity was not inhibited. The measured lactate-to-d-alanine ratio was comparable to the values measured when the l-enantiomer was injected. Metabolites downstream of DAO were not observed when scanning the liver and brain. The conversion of hyperpolarized d-[1-C-13]alanine to lactate and pyruvate was detected in blood ex vivo, and lactate and bicarbonate were detected on scanning the blood pool in the heart in vivo; however, the bicarbonate-to-d-alanine ratio was significantly lower compared with the kidney. These results demonstrate that the specific metabolism of the two enantiomers of hyperpolarized [1-C-13]alanine in the kidney and in the blood can be distinguished, underscoring the potential of d-[1-C-13]alanine as a probe of d-amino acid metabolism.
Nmr In Biomedicine
DOI : 10.1002/nbm.4303
Impact of aerobic exercise type on blood flow, muscle energy metabolism, and mitochondrial biogenesis in experimental lower extremity artery disease
Exercise training (ET) is recommended for lower extremity artery disease (LEAD) management. However, there is still little information on the hemodynamic and metabolic adaptations by skeletal muscle with ET. We examined whether hindlimb perfusion/vascularization and muscle energy metabolism are altered differently by three types of aerobic ET. ApoE−/− mice with LEAD were assigned to one of four groups for 4 weeks: sedentary (SED), forced treadmill running (FTR), voluntary wheel running (VWR), or forced swimming (FS). Voluntary exercise capacity was improved and equally as efficient with FTR and VWR, but remained unchanged with FS. Neither ischemic hindlimb perfusion and oxygenation, nor arteriolar density and mRNA expression of arteriogenic-related genes differed between groups. 18FDG PET imaging revealed no difference in the steady-state levels of phosphorylated 18FDG in ischemic and non-ischemic hindlimb muscle between groups, nor was glycogen content or mRNA and protein expression of glucose metabolism-related genes in ischemic muscle modified. mRNA (but not protein) expression of lipid metabolism-related genes was upregulated across all exercise groups, particularly by non-ischemic muscle. Markers of mitochondrial content (mitochondrial DNA content and citrate synthase activity) as well as mRNA expression of mitochondrial biogenesis-related genes in muscle were not increased with ET. Contrary to FTR and VWR, swimming was ineffective in improving voluntary exercise capacity. The underlying hindlimb hemodynamics or muscle energy metabolism are unable to explain the benefits of running exercise.
DOI : 10.1038/s41598-020-70961-8
Fat navigators based retrospective motion correction strategies for brain magnetic resonance imaging
Magnetic resonance resonance (MRI) is a widely used modality to obtain in vivo tissue information. Clinical applications are near countless, and almost all body parts can be examined using an MR scanner. As the method is non invasive, does not use ionizing radiation and provides excellent soft tissue contrast, it also appears as an excellent tool for neuroscience research. The major drawback of MRI remains the relatively long acquisition times, of the order of several minutes. During the measurement, the subject must stay still and avoid moving at all costs, as otherwise image artefacts will appear and potentially render the acquired data (partially) unusable. As higher image resolution imply longer acquisition time, probing finer anatomical details imply ultimately requires dealing with said motion. While some research goes in the way of reducing the acquisition time, it necessarily comes at the price of lower sensitivity and hence inherently diminishes the achievable gain for high- resolution imaging as the signal is weaker to start with. In this work, the focus is to try and compensate for motion during brain imaging using a navigator method. This amounts to measure not only the desired image, but also other MR based information, called navigator, at regular intervals during the scan. A modeling step then establishes a link between the navigators samples and the head position change. Incorporating the motion information into the main image reconstruction framework helps to retrospectively reduce the impact of said motion and the associated incoherences which would appear during the standard reconstruction. Brain imaging is probably the easiest case of motion correction in MRI, as the motion can readily be well approximated as rigid. The navigator methods developed and investigated in this work, called FatNavs, are based on the fat signal, which in head imaging is very sparse in space and therefore can be imaged rapidly. They also present the advantage of reduced impact on the main image water signal. Several implementation strategies were tested as, due to the versatility of MRI, all image contrasts cannot be ideally navigated using a single general implementation. Applications to inversion recovery based sequences (MP2RAGE) used a well separated navigator and image acquisition scheme. This method being routinely acquired, comparison to Moir Ìe Phase Tracking, the current gold standard for motion tracking and correction, was also performed in collaboration with Hendrik Mattern from the Magdeburg University. For gradient-echo imaging sequences (GRE), on which time-of-flight angiography and susceptibil- ity induced contrasts are based, both separate and mixed acquisition schemes were tested. Further- more, for imaging protocols using long echo time, the fluctuation of the magnetic field during the scan can also induce severe artefacts. Therefore, extension of the FatNavs to a dual-echo field-mapping version was also explored. Finally, combination of FatNavs with FID navigators, which lack spatial information but have much higher temporal resolution, was investigated for both motion and field fluctuation retrospective correction.Lausanne, EPFL, 2020.
DOI : 10.5075/epfl-thesis-9943.
Glutamine-to-glutamate ratio in the nucleus accumbens predicts effort-based motivated performance in humans
Substantial evidence implicates the nucleus accumbens in motivated performance, but very little is known about the neurochemical underpinnings of individual differences in motivation. Here, we applied 1H magnetic resonance spectroscopy (1H-MRS) at ultra-high-field in the nucleus accumbens and inquired whether levels of glutamate (Glu), glutamine (Gln), GABA or their ratios predict interindividual differences in effort-based motivated task performance. Given the incentive value of social competition, we also examined differences in performance under self-motivated or competition settings. Our results indicate that higher accumbal Gln-to-Glu ratio predicts better overall performance and reduced effort perception. As performance is the outcome of multiple cognitive, motor and physiological processes, we applied computational modeling to estimate best-fitting individual parameters related to specific processes modeled with utility, effort and performance functions. This model-based analysis revealed that accumbal Gln-to-Glu ratio specifically relates to stamina; i.e., the capacity to maintain performance over long periods. It also indicated that competition boosts performance from task onset, particularly for low Gln-to-Glu individuals. In conclusion, our findings provide novel insights implicating accumbal Gln and Glu balance on the prediction of specific computational components of motivated performance. This approach and findings can help developing therapeutic strategies based on targeting metabolism to ameliorate deficits in effort engagement.
DOI : 10.1038/s41386-020-0760-6
Study of brain metabolic dysfunctions in animal models of mood disorder using magnetic resonance spectroscopy
Mood disorders, in particular depression, are a major burden of our society. Due to the poor knowledge of the biological basis of these diseases, classification remains based on arbitrary symptomatic parameters. As a result, the existing pharmacological treatments have difficulties targeting relevant pathophysiological processes leading to high level of non-responding patients. Magnetic resonance spectroscopy (MRS) provides an outstanding means of measuring biochemical processes in vivo and can help identifying metabolic pathways that are associated with a given pathological condition. In this thesis, we have taken advantage of state-of-the-art MRS technologies at high field for studying metabolic dysfunctions associated with behavioral impairments in animal models of mood disorder. The overall goal consisted in finding potential biomarkers and endophenotypes (i.e. heritable biomarkers) with MRS, associate them with a molecular/physiological mechanism and evaluate the effect of a treatment targeting the observed dysfunction. We have successfully identified neuroenergetic abnormalities in different limbic regions of the brain in two mouse models of mood disorders; with a genetic or an environmental origin. Genetic deletion of an important metabolic regulator in mouse brain led to hippocampal neuroenergetic impairment and susceptibility to environmental stressors. Treating the animals with ebselen, an energy boosting mood stabilizer, allowed us to reduce the animalâs sensitivity to stress. With the same approach, we observed energy-related biomarkers associated with susceptibility to stress in the nucleus accumbens of genetically identical mice. We found that social hierarchy can predict the response to a chronic stressor and that behavioral impairments could be prevented by administering an energy stimulating compound, acetyl-L-carnitine. Finally, in an additional project, we have used MRS in an embryonic model in ovo to investigate for markers related to metabolic remodeling during neurogenesis. Our results support the idea that mood disorders arise from energy metabolism fragility in different regions of the limbic system with both environmental and genetic origin. Due to the high translational potential of MRS into clinics, our findings provide new biological targets or routes to study for a better understanding of mood disorders.Lausanne, EPFL, 2020.
DOI : 10.5075/epfl-thesis-9820.
Metabolic signature in nucleus accumbens for anti-depressant-like effects of acetyl-L-carnitine
Emerging evidence suggests that hierarchical status provide vulnerability to develop stress-induced depression. Energy metabolic changes in the nucleus accumbens (NAc) were recently related to hierarchical status and vulnerability to develop depression-like behavior. Acetyl-L-carnitine (LAC), a mitochondria-boosting supplement, has shown promising antidepressant-like effects opening therapeutic opportunities for restoring energy balance in depressed patients. We investigated the metabolic impact in the NAc of antidepressant LAC treatment in chronically-stressed mice using (1)H-magnetic resonance spectroscopy ((1)H-MRS). High rank, but not low rank, mice, as assessed with the tube test, showed behavioral vulnerability to stress, supporting a higher susceptibility of high social rank mice to develop depressive-like behaviors. High rank mice also showed reduced levels of several energy-related metabolites in the NAc that were counteracted by LAC treatment. Therefore, we reveal a metabolic signature in the NAc for antidepressant-like effects of LAC in vulnerable mice characterized by restoration of stress-induced neuroenergetics alterations and lipid function.
DOI : 10.7554/eLife.50631
Metabolic and hemodynamic changes in the activated human brain and cerebellar organisation measured by MRS/MRl at 7 Tesla
Although less often investigated than the positive blood-oxygen-level-dependent (BOLD) signal, a negative BOLD signal has also been observed under certain conditions, which could have a neuronal origin. To further investigate the negative BOLD signal from a metabolic point of view, a functional 1H magnetic resonance spectroscopy (fMRS) study was conducted using visual stimulations to trigger a negative BOLD response. The latter was linked to decreases of [Glu] and [Lac] with also a decrease in GABA concentration. These results suggest that the negative BOLD signal is linked to a neuronal deactivation and maybe to a local increase of inhibitory activity. Although both glycolytic and oxidative metabolisms are involved during neuronal activity, it is still unclear how they are respectively modulated by the latter. To investigate this, a functional magnetic resonance imaging (fMRI)-fMRS study was carried out on participants performing a finger tapping task at either 1Hz, 2Hz or 3Hz. In addition to the BOLD signal, the CBF signal was also obtained. As previously observed, the BOLD and CBF signals increased for larger finger tapping frequencies confirming the overall increase of metabolic demand. [Glu] and [Lac] were used as biomarker of oxidative and glycolytic metabolisms, respectively. [Glu] changes were the largest for 3Hz while [Lac] changes were more important at 2Hz. These results highlights the different involvement of the two metabolic pathways. The positive BOLD signal differs in its timings and shape across brain regions. Using a high temporal resolution sequence combined with short stimulations, the positive BOLD responses of six motor regions, including the cerebellum, were extracted. The main difference between motor regions was the positive peak and undershoot amplitudes that were the smallest in the cerebellum, which also showed delayed onsets. In addition to the BOLD response, the cerebellum has some very specific characteristics such as the representation of body parts in both the anterior and posterior lobes. In order to obtain more precise and complete maps of the cerebellar somatotopy, an fMRI motor task was performed testing for the eyes, the tongue, the little fingers, the thumbs or the toes. The anterior lobe showed a consistent and robust somatotopic gradient with also the presence of such a gradient in the posterior lobe, albeit less obvious. These results show that multiple representations of the body are present in the cerebellum and organized in an orderly manner. In addition, the cerebellum can be parcellated based on several features like cell packing, olive fibre input or molecular biomarker. To test whether such tissue characteristics can be observed at macroscale level, T1 and T2* mapping was performed on cerebellar surfaces generated at three different cortical depths. T1 surfaces showed an alternation of lower and higher T1 values when going from the median to the lateral part of the cerebellar hemispheres with shorter T1 values observed in the deeper grey matter layers. T2* maps showed a similar longitudinal pattern, but no change related to the cortical depths. These patterns reflect potential myelin and iron content variations over the cerebellar cortex. Whether these tissue variations are linked to the somatotopic organization is not clear.Lausanne, EPFL, 2020.
DOI : 10.5075/epfl-thesis-9942.
Probiotics Combined With Rifaximin for the Treatment of Chronic Hepatic Encephalopathy: A Longitudinal In Vivo 1H-MRS Study of Brain Metabolism Using BDL Rats2019-09-01. 18th International-Society-for-Hepatic-Encephalopathy-and-Nitrogen-Metabolism Meeting , Williamsburg, VA , Sep 12-15, 2019. p. S19-S19.
DOI : 10.14309/01.ajg.0000582124.67482.93.
Brain Regional Susceptibility to Oxidative Stress in a Rat Model of Chronic Hepatic Encephalopathy: In-Vivo 1H MRS, Ex-Vivo ESR Spectroscopy and Histology Findings2019-09-01. 18th International-Society-for-Hepatic-Encephalopathy-and-Nitrogen-Metabolism Meeting , Williamsburg, VA , Sep 12-15, 2019. p. S33-S36.
Antibiotic Rifaximin for Treatment of Chronic Liver Disease-Induced HE: A Longitudinal In Vivo 1H-MRS Study of Brain Metabolism on BDL Rats2019-09-01. 18th International-Society-for-Hepatic-Encephalopathy-and-Nitrogen-Metabolism Meeting , Williamsburg, VA , Sep 12-15, 2019. p. S18-S19.
DOI : 10.14309/01.ajg.0000582120.59858.08.
Glucose transporter 2 mediates the hypoglycemia-induced increase in cerebral blood flow
Glucose transporter 2 (Glut2)-positive cells are sparsely distributed in brain and play an important role in the stimulation of glucagon secretion in response to hypoglycemia. We aimed to determine if Glut2-positive cells can influence another response to hypoglycemia, i.e. increased cerebral blood flow (CBF). CBF of adult male mice devoid of Glut2, either globally (ripglut1:glut2(-)(/)(-)) or in the nervous system only (NG2KO), and their respective controls were studied under basal glycemia and insulin-induced hypoglycemia using quantitative perfusion magnetic resonance imaging at 9.4 T. The effect on CBF of optogenetic activation of hypoglycemia responsive Glut2-positive neurons of the paraventricular thalamic area was measured in mice expressing channelrhodopsin2 under the control of the Glut2 promoter. We found that in both ripglut1:glut2(-)(/)(-) mice and NG2KO mice, CBF in basal conditions was higher than in their respective controls and not further activated by hypoglycemia, as measured in the hippocampus, hypothalamus and whole brain. Conversely, optogenetic activation of Glut2-positive cells in the paraventricular thalamic nucleus induced a local increase in CBF similar to that induced by hypoglycemia. Thus, Glut2 expression in the nervous system is required for the control of CBF in response to changes in blood glucose concentrations.
Journal Of Cerebral Blood Flow And Metabolism
DOI : 10.1177/0271678X18766743
N-Acetyl-Cysteine Supplementation Improves Functional Connectivity Within the Cingulate Cortex in Early Psychosis: A Pilot Study
Background: There is increasing evidence that redox dysregulation, which can lead to oxidative stress and eventually to impairment of oligodendrocytes and parvalbumin interneurons, may underlie brain connectivity alterations in schizophrenia. Accordingly, we previously reported that levels of brain antioxidant glutathione in the medial prefrontal cortex were positively correlated with increased functional connectivity along the cingulum bundle in healthy controls but not in early psychosis patients. In a recent randomized controlled trial, we observed that 6-month supplementation with a glutathione precursor, N-acetyl-cysteine, increased brain glutathione levels and improved symptomatic expression and processing speed. Methods: We investigated the effect of N-acetyl-cysteine supplementation on the functional connectivity between regions of the cingulate cortex, which have been linked to positive symptoms and processing speed decline. In this pilot study, we compared structural connectivity and resting-state functional connectivity between early psychosis patients treated with 6-month N-acetyl-cysteine (n = 9) or placebo (n = 11) supplementation with sex- and age-matched healthy control subjects (n = 74). Results: We observed that 6-month N-acetyl-cysteine supplementation increases functional connectivity along the cingulum and more precisely between the caudal anterior part and the isthmus of the cingulate cortex. These functional changes can be partially explained by an increase of centrality of these regions in the functional brain network. Conclusions: N-acetyl-cysteine supplementation has a positive effect on functional connectivity within the cingulate cortex in early psychosis patients. To our knowledge, this is the first study suggesting that increased brain glutathione levels via N-acetyl-cysteine supplementation may improve brain functional connectivity.
International Journal of Neuropsychopharmacology
DOI : 10.1093/ijnp/pyz022
Nutritional ketosis increases NAD plus /NADH ratio in healthy human brain: an in vivo study by P-31-MRS2019-07-01. 29th International Symposium on Cerebral Blood Flow, Metabolism and Function / 14th International Conference on Quantification of Brain Function with PET (BRAIN and BRAIN Pet) , Yokohama, JAPAN , Jul 04-07, 2019. p. 209-210.
Evolution of the neurochemical profiles in the G93A-SOD1 mouse model of amyotrophic lateral sclerosis
In vivo (1)H magnetic resonance spectroscopy ((1)H-MRS) investigations of amyotrophic lateral sclerosis (ALS) mouse brain may provide neurochemical profiles and alterations in association with ALS disease progression. We aimed to longitudinally follow neurochemical evolutions of striatum, brainstem and motor cortex of mice transgenic for G93A mutant human superoxide dismutase type-1 (G93A-SOD1), an ALS model. Region-specific neurochemical alterations were detected in asymptomatic G93A-SOD1 mice, particularly in lactate (-19%) and glutamate ( 8%) of brainstem, along with gamma-amino-butyric acid (-30%), N-acetyl-aspartate (-5%) and ascorbate ( 51%) of motor cortex. With disease progression towards the end-stage, increased numbers of metabolic changes of G93A-SOD1 mice were observed (e.g. glutamine levels increased in the brainstem (> 66%) and motor cortex (> 54%)). Through ALS disease progression, an overall increase of glutamine/glutamate in G93A-SOD1 mice was observed in the striatum ( p < 0.01) and even more so in two motor neuron enriched regions, the brainstem and motor cortex ( p < 0.0001). These (1)H-MRS data underscore a pattern of neurochemical alterations that are specific to brain regions and to disease stages of the G93A-SOD1 mouse model. These neurochemical changes may contribute to early diagnosis and disease monitoring in ALS patients.
Journal of Cerebral Blood Flow and Metabolism
DOI : 10.1177/0271678X18756499
Improved off‐resonance phase behavior using a phase‐inverted adiabatic half‐passage pulse for 13 C MRS in humans at 7 T
In vivo (13) C MRS at high field benefits from an improved SNR and spectral resolution especially when using surface coils in combination with adiabatic pulses, such as the adiabatic half-passage (AHP) pulse for (13) C excitation. However, the excitation profile of the AHP pulse is asymmetric relative to the carrier frequency, which could lead to asymmetric excitation of the spectral lines relative to the center of the spectrum. In this study, a pulse-acquire sequence was designed for adiabatic (13) C excitation with a symmetric bandwidth, utilizing a combination of two AHP pulses with inverted phases in alternate scans. Magnetization and phase behavior as a function of frequency offset and RF amplitude of the B1 field, as well as the steady-state transverse magnetization response to off-resonance, were simulated. Excitation properties of the combined pulse sequence were studied by (23) Na imaging and (13) C spectroscopy in vitro on a phantom and in vivo on the human calf at 7 T. Simulations demonstrated symmetric transverse magnetization and phase with respect to positive and negative frequency offsets when using two AHP pulses with inverted phases in alternate scans, thereby minimizing baseline distortion and achieving symmetric T1 weighting, as confirmed by in vitro measurements. The intensities of the lipid peaks at 15, 30, 62, 73, and 130 ppm were in agreement with those theoretically predicted using two AHP pulses with inverted phases in alternate scans. We conclude that using two phase-inverted AHP pulses improves the symmetry of the (13) C excitation profile and phase response to off-resonance effects at 7 T in comparison with using a single AHP pulse.
NMR in Biomedicine
DOI : 10.1002/nbm.4171
Multi-slice passband bSSFP for human and rodent fMRI at ultra-high field
Balanced steady-state free precession (bSSFP) can be used as an alternative to gradient-echo (GE) EPI for BOLD functional MRI when image distortions and signal drop-outs are severe such as at ultra-high field. However, 3D-bSSFP acquisitions have distinct drawbacks on either human or animal MR systems. On clinical scanners, 3D imaging is suboptimal for localized fMRI applications. It can also display distortions when acceleration methods such as spiral read-outs are used, and, compared to multi-slice acquisitions, suffers from increased sensitivity to motion or physiological noise which further results in blurring. On pre-clinical systems, 3D acquisitions have low temporal resolution due to limited acceleration options, while single slice often results in insufficient coverage. The aim of the present study was to implement a multi-slice bSSFP acquisition with Cartesian read-out to obtain non-distorted BOLD fMRI activation maps in the human and rat brain at ultra-high field. We show that, when using a new pseudo-steady-state, the bSSFP signal characteristics are preserved. In the human brain at 7 T, we demonstrate that both task- and resting-state fMRI can be performed with multi-slice bSSFP, with a temporal SNR that matches that of 3D-bSSFP, resulting in - at least - equal performance. In the rat brain at 14 T, we show that the multi-slice bSSFP protocol has similar sensitivity to gradient-echo EPI for task fMRI, while benefitting from much reduced distortions and drop-outs. The advantages of passband bSSFP at 14 T in comparison with GE-EPI are expected to be even more marked for mouse brain.
Journal of Magnetic Resonance
DOI : 10.1016/j.jmr.2019.05.010
Engineering Parallel Transmit/Receive Radio-Frequency Coil Arrays for Human Brain MRI at 7 Tesla
Magnetic resonance imaging is widely used in medical diagnosis to obtain anatomical details of the human body in a non-invasive way. Clinical MR scanners typically operate at a static magnetic field strength (B0) of 1.5T or 3T. However, going to higher field is of great interest since the signal-to-noise ratio is proportional to B0. Therefore, higher image resolution and better contrast between the human tissues could be achieved. Nevertheless, new challenges arise when increasing B0. The wavelength associated with the radio-frequency field B1 has smaller dimensions - approx. 12 cm for human brain tissues - than the human brain itself (20 cm in length), the organ of interest in this thesis. The main consequence is that the transmit field distribution pattern (B1 ) is altered and the final MR images present bright and dark signal spots. These effects prevent the ultra-high field MR scanners (>= 7T) to be used for routine clinical diagnosis. Parallel-transmit is one approach to address these new challenges. Instead of using an RF coil connected to a single power input as it is commonly done at lower magnetic fields, multiple RF coils are used with independent power inputs. The subsequent distinct RF signals can be manipulated separately, which provides an additional degree of freedom to generate homogeneous B1 -field distributions over large or specific regions in the human body. A transmit/receive RF coil array optimized for whole-brain MR imaging was developed and is described in this thesis. Dipoles antennas were used since they could provide a large longitudinal (vertical axis-head to neck) coverage and high transmit field efficiency. Results demonstrated a complete coverage of the human brain, and particularly high homogeneity over the cerebellum. However, since the receive sensitivity over large field-of-views is related to the number of channels available to detect the NMR signal, the next work was to add a 32-channel receive loop coil array to the transmit coil array. The complete coverage of the human brain was assessed with a substantial increase in signal-to-noise compared to the transmit/receive dipole coil array alone. Moreover, acquisition time was shortened since higher acceleration factors could be used. To optimize the individual RF fields and generate an homogeneous B1 -field, a method was developed making use of the particle-swarm algorithm. A user-friendly graphical interface was implemented. Good homogeneity could be achieved over the whole-brain after optimization with the coil array built in this study. Moreover, the optimization was shown to be robust across multiple subjects. The last project was focused on the single transmit system. Local volume coils (single transmit) present pronounced transmit field inhomogeneities in specific regions of the human brain such as the temporal lobes. A widely used approach to address locally these challenges is to add dielectric pads inside the volume coils to enhance the local transmit field efficiency. It was shown in this thesis that constructing dedicated surface coils is a valuable alternative to the dielectric pads in terms of transmit field efficiency and MR spectroscopy results. Two RF coil setups were developed for the temporal and frontal lobes of the human brain, respectively. This thesis provides extensive insight on MR engineering of RF coils at ultra-high field and the potential of parallel-transmit to address the future needs in clinical applications.Lausanne, EPFL, 2019.
DOI : 10.5075/epfl-thesis-9555.
A combined 32‐channel receive‐loops/8‐channel transmit‐dipoles coil array for whole‐brain MR imaging at 7T
Purpose Multichannel receive arrays provide high SNR and parallel‐imaging capabilities, while transmit‐only dipole arrays have been shown to achieve a large coverage of the whole‐brain including the cerebellum. The aim of this study was to develop and characterize the performances of a 32‐channel receive‐only loop array combined with an 8‐channel dipole coil array at 7T for the first time. Methods The 8Tx‐dipoles/32Rx‐loops coil array was characterized by the SNR, g‐factors, noise correlation matrix, accelerated image quality, and urn:x-wiley:07403194:media:mrm27808:mrm27808-math-0003 maps, and compared with a commercial 1Tx‐birdcage/32Rx‐loops array. Simulated and measured urn:x-wiley:07403194:media:mrm27808:mrm27808-math-0004 maps were shown for the 8Tx‐dipoles/32Rx‐loops coil array and compared with the 8Tx/Rx dipole array. Results The in‐house built 32‐channel receive coil demonstrated a large longitudinal coverage of the brain, particularly the upper neck area. G‐factors and accelerated MR acquisitions demonstrated robust performances up to R = 4 in 2D, and R = 8 (4 × 2) in 3D. A 83% increase in SNR was measured over the cerebellum with the in‐house built 8Tx/32Rx coil array compared to the commercial 1Tx/32Rx, while similar performances were obtained in the cerebral cortex. Conclusions The combined 32‐channel receive/8‐channel transmit coil array demonstrated high transmit‐receive performances compared to the commercial receive array at 7T, notably in the cerebellum. We conclude that in combination with parallel transmit capabilities, this coil is particularly suitable for whole‐brain MR studies at 7T.
Magnetic Resonance in Medicine
DOI : 10.1002/mrm.27808
Methodological consensus on clinical proton MRS of the brain: Review and recommendations
Proton MRS (1H MRS) provides noninvasive, quantitative metabolite profiles of tissue and has been shown to aid the clinical management of several brain diseases. Although most modern clinical MR scanners support MRS capabilities, routine use is largely restricted to specialized centers with good access to MR research support. Widespread adoption has been slow for several reasons, and technical challenges toward obtaining reliable good‐quality results have been identified as a contributing factor. Considerable progress has been made by the research community to address many of these challenges, and in this paper a consensus is presented on deficiencies in widely available MRS methodology and validated improvements that are currently in routine use at several clinical research institutions. In particular, the localization error for the PRESS localization sequence was found to be unacceptably high at 3 T, and use of the semi‐adiabatic localization by adiabatic selective refocusing sequence is a recommended solution. Incorporation of simulated metabolite basis sets into analysis routines is recommended for reliably capturing the full spectral detail available from short TE acquisitions. In addition, the importance of achieving a highly homogenous static magnetic field (B0) in the acquisition region is emphasized, and the limitations of current methods and hardware are discussed. Most recommendations require only software improvements, greatly enhancing the capabilities of clinical MRS on existing hardware. Implementation of these recommendations should strengthen current clinical applications and advance progress toward developing and validating new MRS biomarkers for clinical use.
Magnetic Resonance in Medicine
DOI : 10.1002/mrm.27742
Capturing the spatiotemporal dynamics of self-generated, task-initiated thoughts with EEG and fMRI
The temporal structure of self-generated cognition is a key attribute to the formation of a meaningful stream of consciousness. When at rest, our mind wanders from thought to thought in distinct mental states. Despite the marked importance of ongoing mental processes, it is challenging to capture and relate these states to specific cognitive contents. In this work, we employed ultra-high field functional magnetic resonance imaging (fMRI) and high-density electroencephalography (EEG) to study the ongoing thoughts of participants instructed to retrieve self-relevant past episodes for periods of 22sec. These task-initiated, participant-driven activity patterns were compared to a distinct condition where participants performed serial mental arithmetic operations, thereby shifting from self-related to self-unrelated thoughts. BOLD activity mapping revealed selective enhanced activity in temporal, parietal and occipital areas during the memory compared to the mental arithmetic condition, evincing their role in integrating the re-experienced past events into conscious representations during memory retrieval. Functional connectivity analysis showed that these regions were organized in two major subparts, previously associated to “scene-reconstruction” and “self-experience” subsystems. EEG microstate analysis allowed studying these participant-driven thoughts in the millisecond range by determining the temporal dynamics of brief periods of stable scalp potential fields. This analysis revealed selective modulation of occurrence and duration of specific microstates in the memory and in the mental arithmetic condition, respectively. EEG source analysis revealed similar spatial distributions of the sources of these microstates and the regions identified with fMRI. These findings imply a functional link between BOLD activity changes in regions related to a certain mental activity and the temporal dynamics of mentation, and support growing evidence that specific fMRI networks can be captured with EEG as repeatedly occurring brief periods of integrated coherent neuronal activity, lasting only fractions of seconds.
DOI : 10.1016/j.neuroimage.2019.03.029
Metabolite concentration changes associated with positive and negative BOLD responses in the human visual cortex: A functional MRS study at 7 Tesla
Negative blood oxygenation-level dependent (BOLD) signal observed during task execution in functional magnetic resonance imaging (fMRI) can be caused by different mechanisms, such as a blood-stealing effect or neuronal deactivation. Electrophysiological recordings showed that neuronal deactivation underlies the negative BOLD observed in the occipital lobe during visual stimulation. In this study, the metabolic demand of such a response was studied by measuring local metabolite concentration changes during a visual checkerboard stimulation using functional magnetic resonance spectroscopy (fMRS) at 7 Tesla. The results showed increases of glutamate and lactate concentrations during the positive BOLD response, consistent with previous fMRS studies. In contrast, during the negative BOLD response, decreasing concentrations of glutamate, lactate and gamma-aminobutyric acid (GABA) were found, suggesting a reduction of glycolytic and oxidative metabolic demand below the baseline. Additionally, the respective changes of the BOLD signal, glutamate and lactate concentrations of both groups suggest that a local increase of inhibitory activity might occur during the negative BOLD response.
Journal of Cerebral Blood Flow & Metabolism
DOI : 10.1177/0271678X19831022
Investigating the variability of cardiac pulse artifacts across heartbeats in simultaneous EEG-fMRI recordings: A 7T study
Electroencephalography (EEG) recordings performed in magnetic resonance imaging (MRI) scanners are affected by complex artifacts caused by heart function, often termed pulse artifacts (PAs). PAs can strongly compromise EEG data quality, and remain an open problem for EEG-fMRI. This study investigated the properties and mechanisms of PA variability across heartbeats, which has remained largely unaddressed to date, and evaluated its impact on PA correction approaches. Simultaneous EEG-fMRI was performed at 7T on healthy participants at rest or under visual stimulation, with concurrent recordings of breathing and cardiac activity. PA variability was found to contribute to EEG variance with more than 500 muV(2) at 7T, which extrapolates to 92 muV(2) at 3T. Clustering analyses revealed that PA variability not only is linked to variations in head position/orientation, as previously hypothesized, but also, and more importantly, to the respiratory cycle and to heart rate fluctuations. The latter mechanisms are associated to short-timescale variability (even across consecutive heartbeats), and their importance varied across EEG channels. In light of this PA variability, three PA correction techniques were compared: average artifact subtraction (AAS), optimal basis sets (OBS), and an approach based on K-means clustering. All methods allowed the recovery of visual evoked potentials from the EEG data; nonetheless, OBS and K-means tended to outperform AAS, likely due to the inability of the latter in modeling short-timescale variability. Altogether, these results offer novel insights into the dynamics and underlying mechanisms of the pulse artifact, with important consequences for its correction, relevant to most EEG-fMRI applications.
DOI : 10.1016/j.neuroimage.2019.02.021
Underlying mechanisms of episodic autobiographical memory and self-consciousness
Cognitive neuroscience has been examining consciousness associated with the subject, that is the self of the conscious experience and its related multisensory processing of bodily signals, the so-called bodily self-consciousness. Different line of research has highlighted the concept of the autobiographical self in memory and the associated autonoetic consciousness, that is the human ability to mentally travel in time. The subjective re-experiencing of past episodes is often described as re-living them from a viewpoint and location that is similar to the initial encoding. In the first part of my thesis, I have studied how self-relevant bodily cues and personal memories influence our sense of self. In the second part, I have examined how the self is involved in spontaneous thoughts. Through a collection of four studies, I will argue here that it is possible to explore the underlying characteristics of self-consciousness and its relation to bodily signals and memory by a number of cognitive neuroscience approaches, including virtual reality (VR), electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). First, I investigated how the presence or absence of multisensory bodily cues influences long-term episodic autobiographical memory by using immersive VR environment. Second, I examined the underlying brain mechanisms of bodily-self and autobiographical-self by combining a meta-analytical approach with recent fMRI results from (a) patients suffering with out-of-body experiences and (b) healthy participants with induced illusory states of bodily self. Third, I explored how the immersive VR technology can be used to selectively and retroactively strengthen episodic autobiographical memory. Fourth, I examined whether it is possible to capture the inner, self-relevant conscious thoughts and record them with both fMRI and EEG methods. The results from my thesis indicate that (a) the bodily cues fundamentally influence the autobiographical memory and (b) it is possible to manipulate the self-related nature of conscious thoughts. I will discuss my findings with reference to current understanding of bodily-self, autobiographical-self and their links to theories of self-consciousness. Finally, based on my results, I will suggest what should be the following, future step towards memory prosthesis.Lausanne, EPFL, 2019.
DOI : 10.5075/epfl-thesis-9225.
Nucleus accumbens neurochemistry in human anxiety: A 7 T 1H-MRS study
Individual differences in anxiety provide a differential predisposition to develop neuropsychiatric disorders. The neurochemical underpinnings of anxiety remain elusive, particularly in deep structures, such as the nucleus accumbens (NAc) whose involvement in anxiety is being increasingly recognized. We examined the associations between the neurochemical profile of human NAc metabolites involved in neural excitation and inhibition and inter-individual variation in temperamental and situational anxiety. Twenty-seven healthy 20-30 years-old human males were phenotyped with questionnaires for state and trait anxiety (State-Trait Anxiety Inventory, STAI), social anxiety (Liebowitz Social Anxiety Scale), negative mood (Beck Depression Inventory, BDI) and fatigue (Mental and Physical State Energy and Fatigue Scales, SEF). Using proton magnetic resonance spectroscopy ((1)H-MRS) at 7 Tesla (7T), we measured metabolite levels for glutamate, glutamine, GABA and taurine in the NAc. Salivary cortisol was also measured. Strikingly, trait anxiety was negatively associated with NAc taurine content. Perceived situational stress was negatively associated with NAc GABA, while positively with the Glu/GABA ratio. No correlation was observed between NAc taurine or GABA and other phenotypic variables examined (i.e., state anxiety, social anxiety, negative mood, or cortisol), except for a negative correlation between taurine and state physical fatigue. This first 7T study of NAc neurochemistry shows relevant metabolite associations with individual variation in anxiety traits and situational stress and state anxiety measurements. The novel identified association between NAc taurine levels and trait anxiety may pave the way for clinical studies aimed at identifying new treatments for anxiety and related disorders.
DOI : 10.1016/j.euroneuro.2018.12.015
Impact of Caffeine Consumption on Type 2 Diabetes-Induced Spatial Memory Impairment and Neurochemical Alterations in the Hippocampus
Diabetes affects the morphology and plasticity of the hippocampus, and leads to learning and memory deficits. Caffeine has been proposed to prevent memory impairment upon multiple chronic disorders with neurological involvement. We tested whether long-term caffeine consumption prevents type 2 diabetes (T2D)-induced spatial memory impairment and hippocampal alterations, including synaptic degeneration, astrogliosis and metabolic modifications. Control Wistar rats and Goto-Kakizaki (GK) rats that develop T2D were treated with caffeine (1 g/L in drinking water) for four months. Spatial memory was evaluated in a Y-maze. Hippocampal metabolic profile and glucose homeostasis were investigated by 1H magnetic resonance spectroscopy. The density of neuronal, synaptic and glial-specific markers was evaluated by Western blot analysis. GK rats displayed reduced Y-maze spontaneous alternation and a lower amplitude of hippocampal long-term potentiation when compared to controls, suggesting impaired hippocampal-dependent spatial memory. Diabetes did not impact the relation of hippocampal to plasma glucose concentrations, but altered the neurochemical profile of the hippocampus, such as increased in levels of the osmolites taurine (P<0.001) and myo-inositol (P<0.05). The diabetic hippocampus showed decreased density of the pre-synaptic proteins synaptophysin (P<0.05) and SNAP25 (P<0.05), suggesting synaptic degeneration, and increased GFAP (P<0.001) and vimentin (P<0.05) immunoreactivities that are indicative of astrogliosis. The effects of caffeine intake on hippocampal metabolism added to those of T2D, namely reducing myo-inositol levels (P<0.001) and further increasing taurine levels (P<0.05). Caffeine prevented T2D-induced alterations of GFAP, vimentin and SNAP25, and improved memory deficits. We conclude that caffeine consumption has beneficial effects counteracting alterations in the hippocampus of GK rats, leading to the improvement of T2D-associated memory impairment.
Frontiers in Neuroscience
DOI : 10.3389/fnins.2018.01015
High-fat diet consumption alters energy metabolism in the mouse hypothalamus
BACKGROUND/OBJECTIVES: High-fat diet consumption is known to trigger an inflammatory response in the hypothalamus, which has been characterized by an initial expression of pro-inflammatory genes followed by hypothalamic astrocytosis, microgliosis, and the appearance of neuronal injury markers. The specific effects of high-fat diet on hypothalamic energy metabolism and neurotransmission are however not yet known and have not been investigated before. SUBJECTS/METHODS: We used (1)H and (13)C magnetic resonance spectroscopy (MRS) and immunofluorescence techniques to evaluate in vivo the consequences of high-saturated fat diet administration to mice, and explored the effects on hypothalamic metabolism in three mouse cohorts at different time points for up to 4 months. RESULTS: We found that high-fat diet increases significantly the hypothalamic levels of glucose (P < 0.001), osmolytes (P < 0.001), and neurotransmitters (P < 0.05) from 2 months of diet, and alters the rates of metabolic (P < 0.05) and neurotransmission fluxes (P < 0.001), and the contribution of non-glycolytic substrates to hypothalamic metabolism (P < 0.05) after 10 weeks of high-fat feeding. CONCLUSIONS/INTERPRETATION: We report changes that reveal a high-fat diet-induced alteration of hypothalamic metabolism and neurotransmission that is quantifiable by (1)H and (13)C MRS in vivo, and present the first evidence of the extension of the inflammation pathology to a localized metabolic imbalance.
International Journal of Obesity
DOI : 10.1038/s41366-018-0224-9
A human cerebral and cerebellar 8-channel transceive RF dipole coil array at 7T
PURPOSE: Dipole antennas that provide high transmit field penetration with large coverage, and their use in a parallel transmit setup, may be advantageous in minimizing B 1 -field inhomogeneities at ultra-high field, i.e 7T. We have developed and evaluated an 8-channel RF dipole coil array for imaging the entire cerebral and cerebellar regions in man. METHODS: A coil array was modeled with seven dipoles: six placed covering the occipital and temporal lobes; one covering the parietal lobe; and two loops covering the frontal lobe. Center-shortened and fractionated dipoles were simulated for the array configuration and assessed with respect to B 1 -field at maximum specific absorption rate averaged over 10 g tissue regions in human brain. The whole-brain center-shortened dipoles with frontal loops coil array was constructed and its transmit properties were assessed with respect to MR images, B 1 -field, and homogeneity. RESULTS: In simulations, the dipole arrays showed comparable performances to cover the whole-brain. However, for ease of construction, the center-shortened dipole was favored. High spatial resolution anatomical images of the human brain with the coil array demonstrated a full coverage of the cerebral cortex and cerebellum. CONCLUSIONS: The 8-channel center-shortened dipoles and frontal loops coil array promises remarkable efficiency in highly challenging regions as the cerebellum, and phase-only RF shimming of whole-brain could greatly benefit ultra-high field magnetic resonance imaging of the human brain at 7T.
Magnetic Resonance in Medicine
DOI : 10.1002/mrm.27476
Alterations of Brain Energy Metabolism in Type 2 Diabetic Goto-Kakizaki Rats Measured In Vivo by (13)C Magnetic Resonance Spectroscopy
Type 2 diabetes (T2D) is associated with deterioration of brain structure and function. Here, we tested the hypothesis that T2D induces a reorganization of the brain metabolic networks that support brain function. For that, alterations of neuronal and glial energy metabolism were investigated in a T2D model, the Goto-Kakizaki (GK) rat. (13)C magnetic resonance spectroscopy in vivo at 14.1 T was used to detect (13)C labeling incorporation into carbons of glutamate, glutamine, and aspartate in the brain of GK (n = 7) and Wistar (n = 13) rats during intravenous [1,6-(13)C]glucose administration. Labeling of brain glucose and amino acids over time was analyzed with a two-compartment mathematical model of brain energy metabolism to determine the rates of metabolic pathways in neurons and glia. Compared to controls, GK rats displayed lower rates of brain glutamine synthesis (- 32%, P < 0.001) and glutamate-glutamine cycle (- 40%, P < 0.001), and mitochondrial tricarboxylic acid (TCA) cycle rate in neurons (- 7%, P = 0.036). In contrast, the TCA cycle rate of astrocytes was larger in GK rats than controls ( 21%, P = 0.042). We conclude that T2D alters brain energy metabolism and impairs the glutamate-glutamine cycle between neurons and astrocytes, in line with diabetes-induced neurodegeneration and astrogliosis underlying brain dysfunction.
DOI : 10.1007/s12640-017-9821-y
Metabolic And Transcriptional Profiles Of Gbm Invasion: Comparison Of Patients And Paired Patient Derived Xenografts Using1H Magnetic Resonance Spectroscopy And Imaging (7T And 14T) And Rna-Sequencing2018-11-01. 23rd Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO) / 3rd CNS Anticancer Drug Discovery and Development Conference , New Orleans, LA , Nov 14-18, 2018. p. 35-35.
Assessing γ-glutamyl transpeptidase activity in kidney using hyperpolarized γ-Glu-[1-13C]Gly
Hyperpolarized γ-Glu-[1-13C]Gly provides a non-invasive means to detect γ-glutamyl transpeptidase (GGT) enzyme activity in vivo with potential for application in functional imaging. Since GGT is most abundant in the proximal tubules of the kidney, and since the properties of γ-Glu-[1-13C]Gly are suitable for in vivo hyperpolarized 13C metabolic analysis, it was proposed as a molecular probe to study kidney function. The aim of the present study is to identify the dose of γ-Glu-[1-13C]Gly that gives high NMR sensitivity in the unsaturated state of the GGT enzyme. Therefore γ-Glu-[1-13C]Gly was polarized with the stable trityl radical OX63 in a custom-designed DNP polarizer (7T, 1.1K) using microwave irradiation at 196.59 GHz and 50 mW. As a first approach to analyze the HP data, method used in  was applied. Herein, the reaction rates were calculated by multiplying the kinetic rate constants with the corresponding substrate concentrations, in which the kinetic rate constant is the product of the 13C longitudinal relaxation rate of glycine (~45s) and the ratio of the integrated γ-Glu-[1-13C]Gly and [1-13C]Gly signal amplitude. Benefiting from a narrow spectral linewidth of the hyperpolarized signal (~20 Hz, FWHM), conversion of γ-Glu-[1-13C]Gly to [1-13C]Gly was measurable down to an estimated blood concentration of 32 μM. To address the possibility of substrate saturation of the GGT enzyme in the kidney, different doses of γ-Glu-[1-13C]Gly were administered, corresponding to a blood concentration range of 32 to 500 μM. The variability of the apparent reactions rates between animals is high for all doses of administered γ-Glu-[1-13C]Gly. The rate, however, was proportional with the dose in 7 of 8 rats, and complete saturation of the GGT enzyme cannot be seen in the dosage range tested. This study shows that HP γ-GluGly senses GGT activity with excellent NMR sensitivity and that a broad range of substrate concentrations can be applied to study kidney function. To understand better the distribution of the initial reaction rates and to estimate the dose required to saturate the GGT enzyme, a broader range of substrate doses will be tested, along with simultaneous functional quantification.HYP18 Hyperpolarized Magnetic Resonance, Southampton, UK, Septembre 2-5, 2018.
Probing renal pH using hyperpolarized [1-13C]alaninamide
Hyperpolarized molecular probes can be effectively used as pH markers. To date, the only two probes reported in vivo as extracellular pH sensors are 13C-bicarbonate, and [1,5-13C2]zymonic acid. Alaninamide is a derivative of alanine which is found to be sensitive to variations of pH in the physiological range. The aim of the present study was to assess the feasibility of using alaninamide as a pH probe in vivo. The alaninamide titration curve was determined by performing 13C NMR measurements at 9.4 T, 37° on a set of 500 mM Ala-NH2∙HCl samples of varying pH referenced to 13C urea. [1-13C]Alaninamide was polarized at 1 K in a 7 T polarizer, then rapidly dissolved in a buffered solution and injected IV into a Sprague Dawley rat (n=6) located in a 9.4 T animal scanner. 13C FIDs were acquired with 30° BIR4 pulses using a single loop 1H / quadrature 13C surface coil placed over the left kidney. The pH was perturbed by injecting acetazolamide IV (10 mg/kg) one hour prior to infusion. The alaninamide titration curve shows a 13C1 chemical shift change of ≈ 8.4 ppm, and a pKa of 7.9. The pH sensitivity of 13C1 results in three distinct alaninamide spectral peaks, corresponding to three different extracellular pH compartments within the kidney (pH = 7.46, pH = 7.22, pH = 6.58) that can be tentatively assigned to the cortex/blood, medulla and calyx/ureter. With acetazolamide treatment, the pH in the first compartment follows the change in pH of the blood, while the pH in the third compartment does not reflect the urine pH and shifts during the brief experiment. No change is observed in the pH value of the second compartment.HYP18 Hyperpolarized Magnetic Resonance, Southampton, UK, Septembre 2-5, 2018.
Detection of D-amino acid oxidase using hyperpolarized molecular probes
D-amino acid oxidase (DAO) is an enzyme that catalyzes the degradation of D-amino acids in the body. Here, we explored the possibility of detecting D-amino acid oxidase activity by monitoring its metabolism in the rat kidney after a bolus injection of hyperpolarized D-[1-13C]alanine. Our data show that D-alanine is readily converted to lactate only when the DAO enzyme is not inhibited, indicating that the observed metabolism is that of DAO.ISMRM 2018, Paris, France, June 16-21, 2018.
Probing perturbed hepatic metabolism in bile-duct-ligated rats with hyperpolarized 13C pyruvate and arginine
Detoxification of ammonia by the urea cycle and maintenance of glucose homeostasis by gluconeogenesis are two critical functions of the liver. The bile duct ligation (BDL) model of cirrhosis was used to test the ability of hyperpolarized [6-13C]arginine and [1-13C]pyruvate to detect changes in liver function. The conversion of hyperpolarized L-[6-13C]arginine to 13C-urea was observed in a sham-operated rat but not in BDL rats. Striking differences in pyruvate metabolism between the two groups were also noted, indicating that these probes can sense changes in hepatic mitochondrial and cytoplasmic metabolism associated with biliary cirrhosis.ISMRM 2018, Paris, France, June16-21, 2018.
N-acetylcysteine in a Double-Blind Randomized Placebo-Controlled Trial: Toward Biomarker-Guided Treatment in Early Psychosis
DOI : 10.1093/schbul/sbx093
An Add-On Trial With N-Acetyl-Cysteine (Nac) In Early Psychosis Patients: Towards Biomarker Guided Treatment2018. 6th Biennial Conference of the Schizophrenia-International-Research-Society (SIRS) , Florence, ITALY , Apr 04-08, 2018. p. S236-S236.
DOI : 10.1093/schbul/sby017.575.
N-acetylcysteine add-on treatment leads to an improvement of fornix white matter integrity in early psychosis: a double-blind randomized placebo-controlled trial
Mechanism-based treatments for schizophrenia are needed, and increasing evidence suggests that oxidative stress may be a target. Previous research has shown that N-acetylcysteine (NAC), an antioxidant and glutathione (GSH) precursor almost devoid of side effects, improved negative symptoms, decreased the side effects of antipsychotics, and improved mismatch negativity and local neural synchronization in chronic schizophrenia. In a recent double-blind randomized placebo-controlled trial by Conus et al., early psychosis patients received NAC add-on therapy (2700 mg/day) for 6 months. Compared with placebo-treated controls, NAC patients showed significant improvements in neurocognition (processing speed) and a reduction of positive symptoms among patients with high peripheral oxidative status. NAC also led to a 23% increase in GSH levels in the medial prefrontal cortex (GSHmPFC) as measured by (1)H magnetic resonance spectroscopy. A subgroup of the patients in this study were also scanned with multimodal MR imaging (spectroscopy, diffusion, and structural) at baseline (prior to NAC/placebo) and after 6 months of add-on treatment. Based on prior translational research, we hypothesized that NAC would protect white matter integrity in the fornix. A group x time interaction indicated a difference in the 6-month evolution of white matter integrity (as measured by generalized fractional anisotropy, gFA) in favor of the NAC group, which showed an 11% increase. The increase in gFA correlated with an increase in GSHmPFC over the same 6-month period. In this secondary study, we suggest that NAC add-on treatment may be a safe and effective way to protect white matter integrity in early psychosis patients.
DOI : 10.1038/s41398-018-0266-8
Brain metabolism during Chronic Hepatic Encephalopathy studied by in vivo 1H and 31P MRS
Magnetic resonance spectroscopy (MRS) is a powerful tool increasingly used in biomedical research and also in clinical practice. This thesis focused on the improvements of in vivo 31P MRS and 31P magnetization transfer methods at high magnetic field (9.4T). Then, in vivo 31P MRS was combined with 1H MRS to longitudinally study neurometabolic changes during chronic hepatic encephalopathy (CHE) in adult and developing brain using a well-recognized animal model of cholestatic chronic liver disease and HE type C â bile duct ligated (BDL) rats. CHE is neuro-psychiatric disorder caused by chronic liver disease (CLD), with not well-understood molecular mechanisms, inducing important and sometimes lethal brain changes. In a next step, potential protective treatments (probiotics and high creatine diet) were tested. To the best of our knowledge such a detailed approach was not yet published. Firstly, we showed by in vivo 1H MRS in hippocampus that adult BDL rats suffered from increase in brain glutamine, decrease in metabolites involved in osmoregulation including creatine, decrease in neurotransmitters and ascorbate and we were able to show the importance of early metabolic changes compared to late changes thanks to longitudinal measurements. 31P MRS study in larger brain volume found only mild perturbation of energy metabolism such as non-significant trend in ATP decrease in adult BDL rats. Secondly, studies in young BDL rats at two developmental stages by 1H MRS in the hippocampus revealed similar changes that the one observed in adult brain during CHE. However almost all the neurometabolic changes were more profound or appeared earlier in the evolution of the disease in young BDL rats. A new surface 1H-31P double-tuned coil was built and several optimizations and development were done to improve the spectral resolution, SNR and localization, including implementation of 1H-31P NOE enhancement and 1H decoupling in static 31P MRS, optimization of localization method and also development of an optimal protocol for 31P magnetization transfer. 31P MRS study in p21 BDL rats was performed with an improved 31P MRS protocol and revealed a decreased creatine kinase rate constant 2 weeks after BDL surgery and significant changes in metabolites involved in high-phosphate metabolism, in phospholipid metabolism and also cellular redox state 6 weeks after BDL. In the last part of this thesis, some therapeutic approaches were tested. A probiotic treatment delayed some neurometabolic changes present in CHE in adult BDL rats and improved motor activity. Based on previously shown devastating effects of decreased brain creatine during brain development, we proposed the high creatine diet as a possible treatment for young BDL rats. We demonstrated that oral administration of creatine partially restored brain creatine levels and also had a positive effect on other neurometabolic changes present in CHE. In conclusion, the work done in this thesis revealed for the first time a large spectrum of neurometabolic alterations present in adult and young BDL rats suffering from CLD and CHE, together with the time evolution of these changes during the disease progression, using in vivo longitudinal 1H MRS, improved 31P MRS and 31P magnetization transfer protocols developed herein. In addition, we brought some insight on the positive effects of two innovative treatments on the progression of CHE in adult and young BDL rats.Lausanne, EPFL, 2018.
DOI : 10.5075/epfl-thesis-8612.
Nutritional Ketosis Increases NAD /NADH Ratio in Healthy Human Brain: An in Vivo Study by 31P-MRS
Ketones represent an important alternative fuel for the brain under glucose hypo-metabolic conditions induced by neurological diseases or aging, however their metabolic consequences in healthy brains remain unclear. Here we report that ketones can increase the redox NAD /NADH ratio in the resting brain of healthy young adults. As NAD is an important energetic and signaling metabolic modulator, these results provide mechanistic clues on how nutritional ketosis might contribute to the preservation of brain health.
Frontiers in Nutrition
DOI : 10.3389/fnut.2018.00062
In vivo characterization of brain metabolism by 1 H MRS, 13 C MRS and 18 FDG PET reveals significant glucose oxidation of invasively growing glioma cells
Glioblastoma are notorious for their highly invasive growth, diffusely infiltrating adjacent brain structures that precludes complete resection, and is a major obstacle for cure. To characterize this "invisible" tumor part, we designed a high resolution multimodal imaging approach assessing in vivo the metabolism of invasively growing glioma xenografts in the mouse brain. Animals were subjected longitudinally to Magnetic Resonance Imaging (MRI) and (1) H spectroscopy (MRS) at ultra high field (14.1 Tesla) that allowed the measurement of 16 metabolic biomarkers to characterize the metabolic profiles. As expected, the neuronal functionality was progressively compromised as indicated by decreasing N-acetyl aspartate, glutamate and gamma-aminobutyric acid, and reduced neuronal TCA cycle (-58%) and neurotransmission (-50%). The dynamic metabolic changes observed, captured differences in invasive growth that was modulated by reexpression of the tumor suppressor gene WNT inhibitory factor 1 (WIF1) in the orthotopic xenografts that attenuates invasion. At late stage mice were subjected to (13) C MRS with infusion of [1,6-(13) C]glucose and (18) FDG Positron Emission Tomography (PET) to quantify cell-specific metabolic fluxes involved in glucose metabolism. Most interestingly, this provided the first in vivo evidence for significant glucose oxidation in glioma cells. This suggests that the infiltrative front of glioma does not undergo the glycolytic switch per se, but that environmental triggers may induce metabolic reprogramming of tumor cells.
International Journal of Cancer
DOI : 10.1002/ijc.31299
Mapping and characterization of positive and negative BOLD responses to visual stimulation in multiple brain regions at 7T
External stimuli and tasks often elicit negative BOLD responses in various brain regions, and growing experimental evidence supports that these phenomena are functionally meaningful. In this work, the high sensitivity available at 7T was explored to map and characterize both positive (PBRs) and negative BOLD responses (NBRs) to visual checkerboard stimulation, occurring in various brain regions within and beyond the visual cortex. Recently-proposed accelerated fMRI techniques were employed for data acquisition, and procedures for exclusion of large draining vein contributions, together with ICA-assisted denoising, were included in the analysis to improve response estimation. Besides the visual cortex, significant PBRs were found in the lateral geniculate nucleus and superior colliculus, as well as the pre-central sulcus; in these regions, response durations increased monotonically with stimulus duration, in tight covariation with the visual PBR duration. Significant NBRs were found in the visual cortex, auditory cortex, default-mode network (DMN) and superior parietal lobule; NBR durations also tended to increase with stimulus duration, but were significantly less sustained than the visual PBR, especially for the DMN and superior parietal lobule. Responses in visual and auditory cortex were further studied for checkerboard contrast dependence, and their amplitudes were found to increase monotonically with contrast, linearly correlated with the visual PBR amplitude. Overall, these findings suggest the presence of dynamic neuronal interactions across multiple brain regions, sensitive to stimulus intensity and duration, and demonstrate the richness of information obtainable when jointly mapping positive and negative BOLD responses at a whole-brain scale, with ultra-high field fMRI.
Human Brain Mapping
DOI : 10.1002/hbm.24012
Feasibility of in vivo measurement of glucose metabolism in the mouse hypothalamus by (1) H-[(13) C] MRS at 14.1T
PURPOSE: Determine the feasibility of (1) H-[(13) C] MRS in the mouse hypothalamus using a 14.1T magnet. METHODS: We optimized the design of a (1) H-[(13) C] surface coil to maximize the signal-to-noise ratio of (1) H-[(13) C] MRS in the mouse hypothalamus. With enhanced signal, (13) C accumulation in glucose metabolites was measured in a 8.7 microL voxel in the hypothalamus of 5 healthy mice during the continuous administration of [1,6-(13) C2 ]glucose. RESULTS: Accumulation of (13) C label in glucose C6 and lactate C3 was visible in the hypothalamus 11 min after glucose administration. The (13) C fractional enrichment (FE) curves of lactate C3, glutamate and glutamine C4, glutamate glutamine C3 and C2, GABA C2, C3, and C4, and aspartate C3 were measured with a time resolution of 11 min over 190 min. FE time-courses and metabolic pool sizes were averaged to fit a novel one-compartment model of brain energy metabolism that incorporates the main features of the hypothalamus. CONCLUSION: Dynamic (1) H-[(13) C] MRS is able to measure in vivo brain metabolism in small and deep areas of the mouse brain such as the hypothalamus, and it can be used to calculate metabolic fluxes, including glutamatergic and GABAergic metabolism as well as the contribution of metabolic sources other than glucose.
Magnetic Resonance in Medicine
DOI : 10.1002/mrm.27129
Probing cardiac metabolism by hyperpolarized 13C MR using an exclusively endogenous substrate mixture and photo-induced nonpersistent radicals
Purpose To probe the cardiac metabolism of carbohydrates and short chain fatty acids simultaneously in vivo following the injection of a hyperpolarized 13C-labeled substrate mixture prepared using photo-induced nonpersistent radicals. Methods Droplets of mixed [1-13C]pyruvic and [1-13C]butyric acids were frozen into glassy beads in liquid nitrogen. Ethanol addition was investigated as a means to increase the polarization level. The beads were irradiated with ultraviolet light and the radical concentration was measured by ESR spectroscopy. Following dynamic nuclear polarization in a 7T polarizer, the beads were dissolved, and the radical-free hyperpolarized solution was rapidly transferred into an injection pump located inside a 9.4T scanner. The hyperpolarized solution was injected in healthy rats to measure cardiac metabolism in vivo. Results Ultraviolet irradiation created nonpersistent radicals in a mixture containing 13C-labeled pyruvic and butyric acids, and enabled the hyperpolarization of both substrates by dynamic nuclear polarization. Ethanol addition increased the radical concentration from 16 to 26 mM. Liquid-state 13C polarization was 3% inside the pump at the time of injection, and increased to 5% by addition of ethanol to the substrate mixture prior to ultraviolet irradiation. In the rat heart, the in vivo 13C signals from lactate, alanine, bicarbonate, and acetylcarnitine were detected following the metabolism of the injected substrate mixture. Conclusion Copolarization of two different 13C-labeled substrates and the detection of their myocardial metabolism in vivo was achieved without using persistent radicals. The absence of radicals in the solution containing the hyperpolarized 13C-substrates may simplify the translation to clinical use, as no radical filtration is required prior to injection.
Magnetic Resonance in Medicine
DOI : 10.1002/mrm.27122
In Vivo Heteronuclear Magnetic Resonance Spectroscopy
Magnetic Resonance Spectroscopy is a technique that has the capability of measuring metabolites in vivo and, in appropriate conditions, to infer its metabolic rates. The success of MRS depends a lot on its sensitivity, which limits the usage of X-nuclei MRS. However, technological developments and refinements in methods have made in vivo heteronuclear MRS possible in humans and in small animals. This chapter provides detailed descriptions of the main procedures needed to perform successful in vivo heteronuclear MRS experiments, with a particular focus on experimental setup in 13C MRS experiments in rodents.Methods in molecular biology (Clifton, N.J.); Springer,
DOI : 10.1007/978-1-4939-7531-0_11.
Clinical Neuroimaging Using 7 T MRI: Challenges and Prospects
The aim of this article is to illustrate the principal challenges, from the medical and technical point of view, associated with the use of ultrahigh field (UHF) scanners in the clinical setting and to present available solutions to circumvent these limitations. We would like to show the differences between UHF scanners and those used routinely in clinical practice, the principal advantages, and disadvantages, the different UHFs that are ready be applied to routine clinical practice such as susceptibility-weighted imaging, fluid-attenuated inversion recovery, 3-dimensional time of flight, magnetization-prepared rapid acquisition gradient echo, magnetization-prepared 2 rapid acquisition gradient echo, and diffusion-weighted imaging, the technical principles of these sequences, and the particularities of advanced techniques such as diffusion tensor imaging, spectroscopy, and functional imaging at 7TMR. Finally, the main clinical applications in the field of the neuroradiology are discussed and the side effects are reported.
Journal of neuroimaging : official journal of the American Society of Neuroimaging
DOI : 10.1111/jon.12481
Ultra high magnetic field for glial contribution into brain metabolism studied by MR spectroscopy and CEST methods for molecular imaging of glycogen
Magnetic resonance at ultra-high field increases signal and spectral dispersion. In this thesis, I use those characteristics to investigate three different subjects in 13C spectroscopy, hyperpolarized methods and chemical exchange saturation transfer (CEST) used for molecular imaging. In the brain, metabolism is driven by glia-neuron interactions and is composed of at least two compartments with distinct TCA cycle kinetics. The first study examines cerebral metabolic adaptation after an induced glial TCA-cycle impairment using 1H and 13C spectroscopy. We treated rats with fluoroacetate, which specifically blocks glial aconitase and measured changes in neurochemical profile at euglycemic and hyperglycemic condi-tions by in vivo 1H MR spectroscopy. In addition, we evaluated the brain-compartmentalized metabolic adap-tation by following 13C-incorporation into brain amino acids by modern dynamic 13C MRS methods during infu-sion of [1,6-13C2]glucose. By following [1,6-13C2]glucose incorporation, we successfully observed an augmen-tation of pyruvate carboxylase and glutamine synthetase fluxes and a 20% decrease of glial TCA cycle flux. Neuronal metabolism was also affected. In the second study, we focused on hyperpolarized methods to increase acetate 13C polarization allowing us to follow the kinetics of its metabolic products in the TCA cycle. Indeed, infusion of hyperpolarized [1-13C]acetate, an astrocyte-specific precursor, and the in vivo detection of 2-oxo[5-13C]glutarate (2OG), a TCA intermediate, enables the direct analysis of glial Krebs cycle activity. We examined the effect of hyperpolar-ized acetate concentration on its cerebral metabolism and calculate the production rate of 2OG. A healthy group was compared to rodents treated with fluoroacetate. The conversion rates of acetate to 2OG were calculated and were found to depend on the substrate dose. We successfully estimated 2OG production rates. In partially inhibited TCA cycle conditions, the production rate of 2OG was reduced by a quarter. This level of reduction is agrees with the percentage of inhibition calculated in the first study. Finally, we investigated glycogen imaging in skeletal muscle using the CEST strategy. It has been demonstrat-ed in perfused liver that glycogen can be detected indirectly through the water signal using CEST. Glycogen detection is, due to its resonance close to water, strongly sensitive to spectral dispersion and improved by a higher static magnetic field. In contrast to liver, which contains ~300 mmol/g of glycogen and enjoys good glycogen specificity, myocellular content is also rich in creatine, which produces a spectral signal on the same order of amplitude as its glycogen content of ~80-30 mmol/g. In this study, we allowed glycogen to be de-tectable in vivo and distinguishable from the neighboring creatine at 14.1T. We propose to use creatine as an internal reference for muscular glycoCEST analysis. Scanning muscle after physical exercise, resulted in a 50% reduction of glycoCEST compared to muscle at resting state. This result supportis the specificity of the CEST method and is consistent with literature. This last study demonstrates for the first time that glycoCEST imag-ing is feasible in vivo.Lausanne, EPFL, 2018.
DOI : 10.5075/epfl-thesis-8125.
Astrocytic and neuronal oxidative metabolism are coupled to the rate of glutamate-glutamine cycle in the tree shrew visual cortex
Astrocytes play an important role in glutamatergic neurotransmission, namely by clearing synaptic glutamate and converting it into glutamine that is transferred back to neurons. The rate of this glutamate–glutamine cycle (VNT) has been proposed to couple to that of glucose utilization and of neuronal tricarboxylic acid (TCA) cycle. In this study, we tested the hypothesis that glutamatergic neurotransmission is also coupled to the TCA cycle rate in astrocytes. For that we investigated energy metabolism by means of magnetic resonance spectroscopy (MRS) in the primary visual cortex of tree shrews (Tupaia belangeri) under light isoflurane anesthesia at rest and during continuous visual stimulation. After identifying the activated cortical volume by blood oxygenation level-dependent functional magnetic resonance imaging, 1H MRS was performed to measure stimulation-induced variations in metabolite concentrations. Relative to baseline, stimulation of cortical activity for 20 min caused a reduction of glucose concentration by −0.34 ± 0.09 µmol/g (p < 0.001), as well as a −9% ± 1% decrease of the ratio of phosphocreatine-to-creatine (p < 0.05). Then 13C MRS during [1,6-13C]glucose infusion was employed to measure fluxes of energy metabolism. Stimulation of glutamatergic activity, as indicated by a 20% increase of VNT, resulted in increased TCA cycle rates in neurons by 12% ( math formula, p < 0.001) and in astrocytes by 24% ( math formula, p = 0.007). We further observed linear relationships between VNT and both math formula and math formula. Altogether, these results suggest that in the tree shrew primary visual cortex glutamatergic neurotransmission is linked to overall glucose oxidation and to mitochondrial metabolism in both neurons and astrocytes.
DOI : 10.1002/glia.23259
Cannabis use in early psychosis is associated with reduced glutamate levels in the prefrontal cortex
Recent studies have shown that cannabis may disrupt glutamate (Glu) signaling depressing Glu tone in frequent users. Current evidence have also consistently reported lower Glu-levels in various brain regions, particularly in the medial prefrontal cortex (mPFC) of chronic schizophrenia patients, while findings in early psychosis (EP) are not conclusive. Since cannabis may alter Glu synaptic plasticity and its use is a known risk factor for psychosis, studies focusing on Glu signaling in EP with or without a concomitant cannabis-usage seem crucial.
DOI : 10.1007/s00213-017-4745-z
In vivo (13)C MRS in the mouse brain at 14.1 Tesla and metabolic flux quantification under infusion of [1,6-(13)C2]glucose
In vivo (13)C magnetic resonance spectroscopy (MRS) enables the investigation of cerebral metabolic compartmentation while, e.g. infusing (13)C-labeled glucose. Metabolic flux analysis of (13)C turnover previously yielded quantitative information of glutamate and glutamine metabolism in humans and rats, while the application to in vivo mouse brain remains exceedingly challenging. In the present study, (13)C direct detection at 14.1 T provided highly resolved in vivo spectra of the mouse brain while infusing [1,6-(13)C2]glucose for up to 5 h. (13)C incorporation to glutamate and glutamine C4, C3, and C2 and aspartate C3 were detected dynamically and fitted to a two-compartment model: flux estimation of neuron-glial metabolism included tricarboxylic acid cycle (TCA) flux in astrocytes (Vg = 0.16 ± 0.03 µmol/g/min) and neurons (VTCA(n )= 0.56 ± 0.03 µmol/g/min), pyruvate carboxylase activity (VPC = 0.041 ± 0.003 µmol/g/min) and neurotransmission rate (VNT = 0.084 ± 0.008 µmol/g/min), resulting in a cerebral metabolic rate of glucose (CMRglc) of 0.38 ± 0.02 µmol/g/min, in excellent agreement with that determined with concomitant (18)F-fluorodeoxyglucose positron emission tomography ((18)FDG PET).We conclude that modeling of neuron-glial metabolism in vivo is accessible in the mouse brain from (13)C direct detection with an unprecedented spatial resolution under [1,6-(13)C2]glucose infusion.
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
DOI : 10.1177/0271678X17734101
Hyperpolarization of 2-keto[1-13C]isocaproate for in vivo studies with photo-induced radicals
Hyperpolarized 2-keto[1-13C]isocaproate (KIC) provides a means to probe brain nitrogen homeostasis and to assess molecular signatures of tumors. The dynamic nuclear polarization process requires a free-radical polarizing agent, and samples are typically doped with persistent radicals. An alternative is to use photo-induced radicals of α-keto acids that recombine upon dissolution. [1-13C]KIC hyperpolarized with photo-induced radicals could be used to measure the alterations in amino acid metabolism that are linked to neurodegenerative diseases and cancer, and the aim of the present study is to identify the main features that influence the polarization dynamicISMRM 2017, Honolulu, HI, USA, April 22-27, 2017.
Redox dysregulation in schizophrenia pathophysiology: add-on trial with N-acetylcysteine (NAC) in early psychosis patients2017. 30th Congress of the European-College-of-Neuropsychopharmacology (ECNP) , Paris, FRANCE , SEP 02-05, 2017. p. S949-S950.
Cannabis use decreases prefrontal glutamate levels in early psychosis2017. p. S349-S350.
DOI : 10.1016/j.eurpsy.2017.02.324.
N-acetyl-cysteine in a double-blind randomized placebo-controlled trial: Towards biomarker guided treatment in early psychosis2017. p. S806-S806.
DOI : 10.1016/j.eurpsy.2017.01.1560.
Altered glycogen metabolism in the brain of insulin-resistant Goto-Kakizaki rats: a 13C magnetic resonance spectroscopy study in V2017. ISN-ESN Meeting , Paris, FRANCE , AUG 20-24, 2017. p. 216-217.
Investigating mitochondrial biomarkers and function using MRS at 14.1 Tesla in a mouse model of mood disorders2017. ISN-ESN Meeting , Paris, FRANCE , AUG 20-24, 2017. p. 197-198.
Rates oxidative metabolism in astrocytes and neurons are coupled to the glutamate-glutamine cycle in the tree shrew visual cortex2017. ISN-ESN Meeting , Paris, FRANCE , AUG 20-24, 2017. p. 148-148.
Comparison diffusion behavior of metabolites in brains of congenital portal systemic shunt and healthy mice in vivo at 14.1 t2017. ISN-ESN Meeting , Paris, FRANCE , AUG 20-24, 2017. p. 146-146.
Diffusion-weighted MRS of acetate in the rat brain
Acetate has been proposed as an astrocyte-specific energy substrate for metabolic studies in the brain. The determination of the relative contribution of the intracellular and extracellular compartments to the acetate signal using diffusion-weighted magnetic resonance spectroscopy can provide an insight into the cellular environment and distribution volume of acetate in the brain. In the present study, localized (1) H nuclear magnetic resonance (NMR) spectroscopy employing a diffusion-weighted stimulated echo acquisition mode (STEAM) sequence at an ultra-high magnetic field (14.1 T) was used to investigate the diffusivity characteristics of acetate and N-acetylaspartate (NAA) in the rat brain in vivo during prolonged acetate infusion. The persistence of the acetate resonance in (1) H spectra acquired at very large diffusion weighting indicated restricted diffusion of acetate and was attributed to intracellular spaces. However, the significantly greater diffusion of acetate relative to NAA suggests that a substantial fraction of acetate is located in the extracellular space of the brain. Assuming an even distribution for acetate in intracellular and extracellular spaces, the diffusion properties of acetate yielded a smaller volume of distribution for acetate relative to water and glucose in the rat brain.
NMR in biomedicine
DOI : 10.1002/nbm.3768
Influence of physiological noise on accelerated 2D and 3D resting state functional MRI data at 7 T
Physiological noise often dominates the blood-oxygen level-dependent (BOLD) signal fluctuations in high-field functional MRI (fMRI) data. Therefore, to optimize fMRI protocols, it becomes crucial to investigate how physiological signal fluctuations impact various acquisition and reconstruction schemes at different acquisition speeds. In particular, further differences can arise between 2D and 3D fMRI acquisitions due to different encoding strategies, thereby impacting fMRI sensitivity in potentially significant ways.
Magnetic resonance in medicine
DOI : 10.1002/mrm.26823
Social isolation stress and chronic glutathione deficiency have a common effect on the glutamine-to-glutamate ratio and myo-inositol concentration in the mouse frontal cortex
Environmental stress can interact with genetic predisposition to increase the risk of developing psychopathology. In this work, we tested the hypothesis that social isolation stress interacts with impaired glutathione synthesis and have cumulative effects on the neurochemical profile of the frontal cortex. A mouse model with chronic glutathione deficit induced by knockout (-/-) of the glutamate-cysteine ligase modulatory subunit (Gclm) was exposed to social isolation stress from weaning to post-natal day 65. Using magnetic resonance methods at high-field (14.1 T), we analysed the neurochemical profile in the frontal cortex, brain size and ventricular volume of adult animals. Glutathione deficit was accompanied by elevated concentrations of N-acetylaspartate, alanine, and glutamine, as well as the ratio of glutamine to glutamate (Gln/Glu), and by a reduction in levels of myo-inositol and choline-containing compounds in the frontal cortex of -/- animals with respect to wild-type littermates. Although there was no significant interaction between social isolation stress and glutathione deficiency, mice reared in isolation displayed lower myo-inositol concentration (-8.4%, P<0.05) and larger Gln/Glu ( 7.6%, P<0.05), relative to those in group housing. Furthermore, glutathione deficiency caused a reduction of whole brain volume and enlargement of ventricles, but social isolation had no effect on these parameters. We conclude that social isolation caused neurochemical alterations that may add to those associated to impaired glutathione synthesis. This article is protected by copyright. All rights reserved.
Journal of neurochemistry
DOI : 10.1111/jnc.14116
Sexual dimorphism in hepatic lipids is associated with the evolution of metabolic status in mice
Ectopic lipid accumulation in the liver is implicated in metabolic disease in an age- and sex-dependent manner. The role of hepatic lipids has been well established within the scope of metabolic insults in mice, but has been insufficiently characterized under standard housing conditions, where age-related metabolic alterations are known to occur. We studied a total of 10 male and 10 female mice longitudinally. At 3, 7 and 11 months of age, non-invasive (1) H-magnetic resonance spectroscopy ((1) H-MRS) was used to monitor hepatic lipid content (HLC) and fatty acid composition in vivo, and glucose homeostasis was assessed with glucose and insulin challenges. At the end of the study, hepatic lipids were comprehensively characterized by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometric analyses of liver tissue samples. In males, HLC increased from 1.4 ± 0.1% at 3 months to 2.9 ± 0.3% at 7 months (p < 0.01) and 2.7 ± 0.3% at 11 months (p < 0.05), in correlation with fasting insulin levels (p < 0.01, r = 0.51) and parameters from the insulin tolerance test (ITT; p < 0.001, r = -0.69 versus area under the curve; p < 0.01, r = -0.57 versus blood glucose drop at 1 h post-ITT; p < 0.01, r = 0.55 versus blood glucose at 3 h post-ITT). The metabolic performance of females remained the same throughout the study, and HLC was higher than that of males at 3 months (2.7 ± 0.2%, p < 0.01), but comparable at 7 months (2.2 ± 0.2%) and 11 months (2.2 ± 0.1%). Strong sexual dimorphism in bioactive lipid species, including diacylglycerols (higher in males, p < 0.0001), phosphatidylinositols (higher in females, p < 0.001) and omega-3 polyunsaturated fatty acids (higher in females, p < 0.01), was found to be in good correlation with metabolic scores at 11 months. Therefore, in mice housed under standard conditions, sex-specific composition of bioactive lipids is associated with metabolic protection in females, whose metabolic performance was independent of hepatic cytosolic lipid content.
NMR in biomedicine
DOI : 10.1002/nbm.3761
Hierarchical status predicts behavioral vulnerability and nucleus accumbens metabolic profile following chronic social defeat stress.
Extensive data highlight the existence of major differences in individuals’ susceptibility to stress [1; 2; 3 ; 4]. While genetic factors [5 ; 6] and exposure to early life stress [7 ; 8] are key components for such neurobehavioral diversity, intriguing observations revealed individual differences in response to stress in inbred mice [9; 10; 11 ; 12]. This raised the possibility that other factors might be critical in stress vulnerability. A key challenge in the field is to identify non-invasively risk factors for vulnerability to stress. Here, we investigated whether behavioral factors, emerging from preexisting dominance hierarchies, could predict vulnerability to chronic stress [9; 13; 14; 15 ; 16]. We applied a chronic social defeat stress (CSDS) model of depression in C57BL/6J mice to investigate the predictive power of hierarchical status to pinpoint which individuals will exhibit susceptibility to CSDS. Given that the high social status of dominant mice would be the one particularly challenged by CSDS, we predicted and found that dominant individuals were the ones showing a strong susceptibility profile as indicated by strong social avoidance following CSDS, while subordinate mice were not affected. Data from 1H-NMR spectroscopy revealed that the metabolic profile in the nucleus accumbens (NAc) relates to social status and vulnerability to stress. Under basal conditions, subordinates show lower levels of energy-related metabolites compared to dominants. In subordinates, but not dominants, levels of these metabolites were increased after exposure to CSDS. To the best of our knowledge, this is the first study that identifies non-invasively the origin of behavioral risk factors predictive of stress-induced depression-like behaviors associated with metabolic changes.
DOI : 10.1016/j.cub.2017.06.027
Metabolite concentration changes during increase of the BOLD signal in the human visual cortex: a functional magnetic resonance spectroscopy study at 7T2017. 28th International Symposium on Cerebral Blood Flow, Metabolism and Function / 13th International Conference on Quantification of Brain Function with PET , Int Soc Cerebral Blood Flow & Metab, Berlin, GERMANY , APR 01-04, 2017. p. 503-504.
Defining mitochondrial biomarkers and function using magnetic resonance spectroscopy at 14.1 Tesla in a mouse model of mood disorders2017. 28th International Symposium on Cerebral Blood Flow, Metabolism and Function / 13th International Conference on Quantification of Brain Function with PET , Int Soc Cerebral Blood Flow & Metab, Berlin, GERMANY , APR 01-04, 2017. p. 494-494.
In vivo detection of hypothalamic glucose metabolism in HFD and regular fed mice2017. 28th International Symposium on Cerebral Blood Flow, Metabolism and Function / 13th International Conference on Quantification of Brain Function with PET , Int Soc Cerebral Blood Flow & Metab, Berlin, GERMANY , APR 01-04, 2017. p. 443-444.
Glucose and glycogen metabolism in the brain of insulin resistant Goto-Kakizaki rats2017. 28th International Symposium on Cerebral Blood Flow, Metabolism and Function / 13th International Conference on Quantification of Brain Function with PET , Int Soc Cerebral Blood Flow & Metab, Berlin, GERMANY , APR 01-04, 2017. p. 417-417.
Coupling of the glutamate-glutamine cycle rate with both glial and neuronal oxidative metabolism in the visual cortex of the Tupaia belangeri2017. 28th International Symposium on Cerebral Blood Flow, Metabolism and Function / 13th International Conference on Quantification of Brain Function with PET , Int Soc Cerebral Blood Flow & Metab, Berlin, GERMANY , APR 01-04, 2017. p. 60-60.
How Energy Metabolism Supports Cerebral Function: Insights from 13C Magnetic Resonance Studies In vivo
Cerebral function is associated with exceptionally high metabolic activity, and requires continuous supply of oxygen and nutrients from the blood stream. Since the mid-20th century the idea that brain energy metabolism is coupled to neuronal activity has emerged, and a number of studies supported this hypothesis. Moreover, brain energy metabolism was demonstrated to be compartmentalized in neurons and astrocytes, and astrocytic glycolysis was proposed to serve the energetic demands of glutamatergic activity. Shedding light on the role of astrocytes in brain metabolism, the earlier picture of astrocytes being restricted to a scaffold-associated function in the brain is now out of date. With the development and optimization of non-invasive techniques, such as nuclear magnetic resonance spectroscopy (MRS), several groups have worked on assessing cerebral metabolism in vivo. In this context, 1H MRS has allowed the measurements of energy metabolism-related compounds, whose concentrations can vary under different brain activation states. 1H-[13C] MRS, i.e. indirect detection of signals from 13C-coupled 1H, together with infusion of 13C-enriched glucose has provided insights into the coupling between neurotransmission and glucose oxidation. Although these techniques tackle the coupling between neuronal activity and metabolism, they lack chemical specificity and fail in providing information on neuronal and glial metabolic pathways underlying those processes. Currently, the improvement of detection modalities (i.e. direct detection of 13C isotopomers), the progress in building adequate mathematical models along with the increase in magnetic field strength now available, render possible detailed compartmentalized metabolic flux characterization. In particular, direct 13C MRS offers more detailed dataset acquisitions and provide information on metabolic interactions between neurons and astrocytes, and their role in supporting neurotransmission. Here we review state-of-the-art MR methods to study brain function and metabolism in vivo, and their contribution to the current understanding of how astrocytic energy metabolism supports glutamatergic activity and cerebral function. In this context, recent data suggests that astrocytic metabolism has been underestimated. Namely, the rate of oxidative metabolism in astrocytes is about half of that in neurons, and it can increase as much as the rate of neuronal metabolism in response to somatosensory stimulation.
Frontiers in Neuroscience
DOI : 10.3389/fnins.2017.00288
Study of cortical energy metabolism during sensory stimulation-induced brain activity by ¹³C magnetic resonance spectroscopy in vivo
Cerebral function is associated with high metabolic activity that is supported by continuous supply of oxygen and glucose from the blood. Coupling between brain energy metabolism and neuronal activity has been studied extensively during the past decades. Notably, glucose metabolism was demonstrated to result from cellular cooperation between neurons and astrocytes. Although both cell types regulate synaptic transmission via the glutamate-glutamine cycle, the actual contribution of glial and neuronal oxidative metabolism is still unclear. Several research groups have tried to quantify cerebral energy metabolism in the living brain using methods, such as positron emission tomography, autoradiography and proton magnetic resonance spectroscopy (1H MRS). Yet, these methods lack chemical specificity and do not provide quantitative information specific to either cell types. The development of tracers detectable by MRS, such as 13C isotope, along with high magnetic field and dedicated hardware systems has improved sensitivity and has motivated the design of advanced metabolic modeling, in which cell types can be compartmentalized and which associated metabolic rates can be assessed independently of any prior estimations. The work of this thesis aimed at focally increasing neuronal activity and estimating the resulting changes in glial and neuronal oxidative metabolism using direct 13C MRS along with [1,6-13C]glucose infusion in vivo at 14.1 T. 4h-somatosensory stimulation paradigm was first developed in rats under alpha-chloralose. The protocol consisted on intermittently electrically stimulating both fore- and hindpaws, which resulted in a sustained and localized blood oxygenation level-dependent signal as assessed by functional magnetic resonance imaging. The relatively large activated area in the cortex allowed monitoring local 13C isotope incorporation over 4h into specific positions of glutamate, glutamine and aspartate. The analysis of the turnover curves with a two-compartment model of brain energy metabolism revealed an increase of both glial (VTCAg, 68 nmol/g/min, 22%) and neuronal (VTCAn, 62 nmol/g/min, 12%) oxidative metabolism associated with 95% increase (VNT, 67 nmol/g/min) in glutamate-glutamine cycle rate, which represents glutamatergic neurotransmission rate. The total increase in glucose oxidative metabolism was of 15% (CMRglc(ox), 67 nmol/g/min). In randomly delivering lines in 4 orientations and 2 directions, 4h-continuous stimulation of tree shrew primary visual cortex under light isoflurane anesthesia resulted in a decrease in both brain glucose concentration (-17%;-0.34 µmol/g) and phosphocreatine/creatine ratio (-9%;-0.07) after 16 minutes of stimulation onset, which recovered 21 minutes after stimulation offset. At the individual level, a nearly one-to-one relationships between VNT and CMRglc(ox) was observed. VTCAn and VTCAg were also coupled to VNT. At the group level, 20% increase in VNT ( 0.038±0.042 µmol/g/min) resulted in 24% ( 0.063±0.057 µmol/g/min) and 12% ( 0.061±0.032 µmol/g/min) increase in VTCAg and VTCAn, respectively, resulting in 14% increase in CMRglc(ox) ( 0.058±0.032 µmol/g/min). To conclude, this work demonstrates that a significant fraction of glucose is also oxidized in astrocytes and that both neuronal and astrocytic metabolism can be stimulated by and coupled to the glutamate-glutamine cycle rate.Lausanne, EPFL, 2017.
DOI : 10.5075/epfl-thesis-7684.
N-Acetyl-Cysteine In A Doubleblind Randomized Placebo-Controlled Trial: Toward Biomarker-Guided Treatment In Early Psychosis2017. 16th International Congress on Schizophrenia Research (ICOSR) , San Diego, CA , MAR 24-28, 2017. p. S119-S120.
In vivo cerebral metabolism of glioblastoma xenografts assessed with ¹H MRS, ¹³C MRS and ¹⁸F-FDG PET
Magnetic resonance spectroscopy (MRS) is a powerful tool when studying metabolism in intact and living organs preserving cells in their natural microenvironment with minimal external interference. The unique insights offered by the observation of metabolic processes in vivo are available thanks to the non-invasiveness of the MR technique, due to the employment of non-ionizing radiations at room temperature. These conditions are ideal when studying cerebral metabolism in vivo, since the brain is a particularly complex organ where neurons and glial cells are highly interconnected and dependent from each other. Moreover, brain cells are protected by the blood-brain barrier, which regulates the delivery of nutrients and chemicals. The work of this thesis focused on the application of 1H and 13C MRS in vivo to study cerebral metabolism in mice. 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) was used in complement to the abovementioned MR techniques to determine the cerebral metabolic rate of glucose (CMRglc) or local glucose uptake under specific physiological and pathological conditions. At first, we validated the application of 13C MRS to small volumes in the mouse brain in combination to compartmental modeling for neuro-glial metabolism, as previously applied to humans and rats in larger volumes. The second part of the thesis focused on the translation of these techniques to the study of brain metabolism during glioblastoma invasion. A highly infiltrative mouse xenograft model of glioblastoma derived from human glioma spheres was employed in our study to determine the evolution over time of the neurochemical profile detected with 1H MRS at 14.1 Tesla. 13C-labeling experiments with [1,6-13C]glucose were performed at late stage after extensive glioma invasion in the whole brain. Metabolic fluxes were determined under these conditions reflecting energetic metabolism in neurons and glioma/glial cells. Globally, infiltrating cells did not show a highly glycolytic metabolism, as often observed in cancer cells and in glioma cells close to the tumor core, suggesting that environmental stimuli induced by a central necrosis, high cellular density and poor vascularization may be crucial to the occurrence of a metabolic switch. Finally, a novel patient-derived mouse xenograft model of glioblastoma was tested and characterized longitudinally with 1H MRS at 14.1 Tesla. Glioma cells were implanted intracranially after patient tumor resection and minimal manipulation in vitro in order to minimize a selective pressure and promote a close resemblance of the xenograft with the parental tumor. This study showed that patient-derived xenografts obtained from freshly injected glioma cells offer a reliable model to study glioma invasion and related treatments while raising intriguing questions on the mechanisms of adaptation of human cells to the brain of the host.Lausanne, EPFL, 2017.
DOI : 10.5075/epfl-thesis-7667.
Energy metabolism in the rat cortex under thiopental anaesthesia measured
Barbiturates, commonly used as general anaesthetics, depress neuronal activity and thus cerebral metabolism. Moreover, they are likely to disrupt the metabolic support of astrocytes to neurons, as well as the uptake of nutrients from circulation. By employing 13C magnetic resonance spectroscopy (MRS) in vivo at high magnetic field, we characterized neuronal and astrocytic pathways of energy metabolism in the rat cortex under thiopental anaesthesia. The neuronal tricarboxylic acid (TCA) cycle rate was 0.46 ± 0.02 µmol/g/min, and the rate of the glutamate-glutamine cycle was 0.09 ± 0.02 µmol/g/min. In astrocytes, the TCA cycle rate was 0.16 ± 0.02 µmol/g/min, accounting for a quarter of whole brain glucose oxidation, pyruvate carboxylase rate was 0.02 ± 0.01 µmol/g/min, and glutamine synthetase was 0.12 ± 0.01 µmol/g/min. Relative to previous experiments under light α-chloralose anaesthesia, thiopental reduced oxidative metabolism in neurons and even more so in astrocytes. Interestingly, total oxidative metabolism in the cortex under thiopental anaesthesia surpassed the rate of pyruvate production by glycolysis, indicating substantial utilisation of substrates other than glucose, likely plasma lactate.
Journal of Neuroscience Research
DOI : 10.1002/jnr.24032
Progress towards in vivo brain (13)C-MRS in mice: Metabolic flux analysis in small tissue volumes
The combination of dynamic (13)C MRS data under infusion of (13)C-labeled substrates and compartmental models of cerebral metabolism enabled in vivo measurement of metabolic fluxes with a quantitative and distinct determination of cellular-specific activities. The non-invasive nature and the chemical specificity of the (13)C dynamic data obtained in those tracer experiments makes it an attractive approach offering unique insights into cerebral metabolism. Genetically engineered mice present a wealth of disease models particularly interesting for the neuroscience community. Nevertheless, in vivo(13)C NMR studies of the mouse brain are only recently appearing in the field due to the numerous challenges linked to the small mouse brain volume and the difficulty to follow the mouse physiological parameters within the NMR system during the infusion experiment. This review will present the progresses in the quest for a higher in vivo(13)C signal-to-noise-ratio up to the present state of the art techniques, which made it feasible to assess glucose metabolism in different regions of the mouse brain. We describe how experimental results were integrated into suitable compartmental models and how a deep understanding of cerebral metabolism depends on the reliable detection of (13)C in the different molecules and carbon positions.
DOI : 10.1016/j.ab.2017.01.019
Glycogen Supercompensation in the Rat Brain After Acute Hypoglycemia is Independent of Glucose Levels During Recovery
Patients with diabetes display a progressive decay in the physiological counter-regulatory response to hypoglycemia, resulting in hypoglycemia unawareness. The mechanism through which the brain adapts to hypoglycemia may involve brain glycogen. We tested the hypothesis that brain glycogen supercompensation following hypoglycemia depends on blood glucose levels during recovery. Conscious rats were submitted to hypoglycemia of 2 mmol/L for 90 min and allowed to recover at different glycemia, controlled by means of i.v. glucose infusion. Brain glycogen concentration was elevated above control levels after 24 h of recovery in the cortex, hippocampus and striatum. This glycogen supercompensation was independent of blood glucose levels in the post-hypoglycemia period. In the absence of a preceding hypoglycemia insult, brain glycogen concentrations were unaltered after 24 h under hyperglycemia. In the hypothalamus, which controls peripheral glucose homeostasis, glycogen levels were unaltered. Overall, we conclude that post-hypoglycemia glycogen supercompensation occurs in several brain areas and its magnitude is independent of plasma glucose levels. By supporting brain metabolism during recurrent hypoglycemia periods, glycogen may have a role in the development of hypoglycemia unawareness.
DOI : 10.1007/s11064-017-2178-z
Technical and experimental features of Magnetic Resonance Spectroscopy of brain glycogen metabolism
In the brain, glycogen is a source of glucose not only in emergency situations but also during normal brain activity. Altered brain glycogen metabolism is associated with energetic dysregulation in pathological conditions, such as diabetes or epilepsy. Both in humans and animals, brain glycogen levels have been assessed non-invasively by Carbon-13 Magnetic Resonance Spectroscopy (13C-MRS) in vivo. With this approach, glycogen synthesis and degradation may be followed in real time, thereby providing valuable insights into brain glycogen dynamics. However, compared to the liver and muscle, where glycogen is abundant, the sensitivity for detection of brain glycogen by 13C-MRS is inherently low. In this review we focus on strategies used to optimize the sensitivity for 13C-MRS detection of glycogen. Namely, we explore several technical perspectives, such as magnetic field strength, field homogeneity, coil design, decoupling, and localization methods. Furthermore, we also address basic principles underlying the use of 13C-labeled precursors to enhance the detectable glycogen signal, emphasizing specific experimental aspects relevant for obtaining kinetic information on brain glycogen.
DOI : 10.1016/j.ab.2016.12.023
Studying cyto and myeloarchitecture of the human cortex at ultra-high field with quantitative imaging: R1, R⁎2 and susceptibility
In this manuscript, the use of quantitative imaging at ultra-high field is evaluated as a mean to study cyto and myelo-architecture of the cortex. The quantitative contrasts used are the longitudinal relaxation rate (R1), apparent transverse relaxation rate (R2⁎) and quantitative susceptibility mapping (QSM). The quantitative contrasts were computed using high resolution in-vivo (0.65mm isotropic) brain data acquired at 7 T. The performance of the different quantitative approaches was evaluated by visualizing the contrast between known highly myelinated primary sensory cortex regions and the neighbouring cortex. The transition from the inner layers to the outer layers (from white matter to the pial surface) of the human cortex, which is known to have varying cyto- and myelo architecture, was evaluated. The across cortex and through depth behaviour observed for the different quantitative maps was in good agreement between the different subjects, clearly allowing the differentiation between different Brodmann regions, suggesting these features could be used for individual cortical brain parcellation. While both R1 and R2⁎ maps decrease monotonically from the white matter to the pial surface due to the decrease of myelin and iron between these regions, magnetic susceptibility maps have a more complex behaviour reflecting its opposing sensitivity to myelin and iron concentration.
DOI : 10.1016/j.neuroimage.2016.12.009
Prospective head motion correction using FID-guided on-demand image navigators
PURPOSE: We suggest a motion correction concept that employs free-induction-decay (FID) navigator signals to continuously monitor motion and to guide the acquisition of image navigators for prospective motion correction following motion detection. METHODS: Motion causes out-of-range signal changes in FID time series that, and in this approach, initiate the acquisition of an image navigator. Co-registration of the image navigator to a reference provides rigid-body-motion parameters to facilitate prospective motion correction. Both FID and image navigator are integrated into a prototype magnetization-prepared rapid gradient-echo (MPRAGE) sequence. The performance of the method is investigated using image quality metrics and the consistency of brain volume measurements. RESULTS: Ten healthy subjects were scanned (a) while performing head movements (nodding, shaking, and moving in z-direction) and (b) to assess the co-registration performance. Mean absolute errors of 0.27 /- 0.38 mm and 0.19 /- 0.24 degrees for translation and rotation parameters were measured. Image quality was qualitatively improved after correction. Significant improvements were observed in automated image quality measures and for most quantitative brain volume computations after correction. CONCLUSION: The presented method provides high sensitivity to detect head motion while minimizing the time invested in acquiring navigator images. Limits of this implementation arise from temporal resolution to detect motion, false-positive alarms, and registration accuracy.
Magnetic resonance in medicine
DOI : 10.1002/mrm.26364
N-Acetyl-Cysteine in a double-blind randomized placebo-controlled trial: Towards biomarker guided treatment in early psychosis2016. p. 175-175.
Proton diffusion spectroscopy and modeling of brain metabolism at 14.1T
As a field at the CIBM, Nuclear magnetic resonance (NMR)spectroscopy can be applied non-invasively to explore the metabolic fate of energy fuel substrates, as well as the rate at which they are consumed, using 13C and 1H nuclei. The work of this thesis encompasses both nuclei, and focuses on (1) improving the quantification and modeling of glucose-derived metabolites; and (2) characterizing diffusion-related parameters of the purportedly glial-specific energy substrate, acetate. Both aim to quantitatively explore cerebral energy metabolism, at ultra-high magnetic field, in vivo, in the healthy rat. 13C NMR spectroscopy, as a tool, enables measuring the progressive incorporation of 13C-glucose into brain glucose and then NMR detectable amino acids (glutamate and glutamine); this relies on the infusion of the 13C-labeled energy substrate. The experimentally obtained 13C labelling curves are analyzed using suitable mathematical models to provide an estimation of cerebral metabolic rates. Here, a dynamic model of time-courses of 13C multiplets arising from isotopomers was considered. So beyond the two-compartment neuronal-glial model, we took into account additional data on the dynamics of 13C isotopomers, available from the fine structure multiplets in 13C spectra of glutamate and glutamine, measured under prolonged [1-6,13C] glucose infusion. We concluded that the dynamic analyses of 13C multiplet time courses of glutamate and glutamine resulted in a higher precision for estimating the absolute values of most cerebral metabolic rates. Acetate metabolism is challenging because dynamic metabolic modeling requires prior knowledge of the transport and uptake kinetics of infused acetate. We sought this information by determining the apparent concentration and distribution volume (V_d) of cerebral acetate between the intracellular and the extracellular compartments. Experimentally, the diffusion characteristics of cerebral acetate were measured, relative to that of N-Acetylaspartate (NAA, known to be mainly intracellular) using diffusion-weighted 1H NMR spectroscopy at 14.1T, under prolonged acetate infusion. The detection of an acetate and NAA signal at large diffusion weighting provided direct experimental evidence of intracellular cerebral acetate and NAA, although a substantial fraction of acetate was extracellular. To estimate the apparent concentration of in vivo brain acetate, T1 and T2 relaxation times of acetate were measured. The longer T1 relaxation and shorter T2 relaxation times of acetate compared with NAA provided evidence of its small molecular size, and possibly different chemical environment. Our experimentally determined value of V_dled to cerebral metabolic rates of acetate (CMR acetate) of the same order reported for the glial Krebâs cycle rate, an indication that estimates of CMR acetate are highly dependent on V_d. Finally, in order to pursue metabolic mapping of cerebral acetate uptake in the rat, in vivo, at 14.1 T, the design and construction of a combined transmit-birdcage coil and receive-quadrature pair surface coil was considered. Its performance was compared to a single birdcage coil in the transmit/receive mode. So far, the preliminary results of the 2-coil configuration are promising: homogenous excitation and a gain in sensitivity up to a distance of 5 mm are achievable. Improvements are ongoing for NMR spectroscopic and imaging applications at 14.1 T.Lausanne, EPFL, 2016.
DOI : 10.5075/epfl-thesis-7275.
Quantitative Susceptibility Mapping in the Human Brain
Magnetic resonance imaging (MRI) offers a good tissue contrast and the ability to visualize many disease related morphologies. The work presented in this thesis investigates the study of underlying structure of the brain using quantitative methods with a special emphasis on quantitative susceptibility mapping (QSM). Magnetic susceptibility reflects the interaction of a material to the magnetic field and measures in biological tissues the magnetic susceptibility of inclusions. The reconstruction of QSM requires further processing steps as the magnetic field produced by the sources needs to be disentangled from the orders of magnitude bigger background field. The produced field also depends not only on the shape and the orientation, but also on the anisotropy of susceptibility and the microstructural compartmentalization of the biological source. For this reason, reconstruction methods need to be capable to calculate accurate values for different brain regions as well as applicable in the everyday clinical diagnosis. Within the framework of the thesis a data acquisition protocol based on a multiple-echo gradient echo sequence as well as a post-processing protocol was implemented. One of the processing steps, the background removal method, was applied to preserve the brain regions close to the cerebrospinal fluid (CSF). This method outperforms state of the art methods in this regions but is computationally intensive. Different brain regions were studied using quantitative methods with special emphasis on the QSM. A new method, modulated closed form solution, with extremely fast computational time is proposed. The comparison with other single orientation methods revealed similar results and the highest correlation to the state-of-the-art method (COSMOS) in the deep gray matter. The R2* maps calculated from the same dataset are also able to distinguish the deep gray matter structures with a similar quality. However, QSM shows a higher sensitivity in early stage multiple sclerosis lesions as well as white matter-gray matter structures. In the human cortex the obtained cortical maps show enhancement of primary sensory cortex, which is known to be highly myelinated, on three evaluated quantitative contrasts R1,R2* and susceptibility. The contrasts based on the relaxation rates, R1 and R2*, show a monotonically decrease from the white matter to the CSF imitating the decrease in iron and myelin. The susceptibility behaviour is more complex as iron and myelin content introduce an opposing sensitivity, allowing to study iron and myelin content when combining the three contrasts. The microstructural organization of white matter influences the R2*, R2 as well as field map from which QSM is calculated. This structure leads to an orientation dependence of the studied contrasts and for QSM the spherical assumption is not valid anymore. Therefore a new QSM method is introduced, which includes the Lorentzian correction in white matter. Main fibres such as forceps major and minor were analysed for the three different quantitative contrasts. The anisotropic component associated with susceptibility is similar for the relaxation rates whereas the isotropic component of R2* shows a higher variability. The resulting deep gray matter structure of the new QSM method remained similar to the state-of-the-art method when comparing the isotropic component but calculates physically meaningful susceptibility maps with improved contrast between known fibre bundles.Lausanne, EPFL, 2016.
DOI : 10.5075/epfl-thesis-7050.
Early detection of human glioma sphere xenografts in mouse brain using diffusion MRI at 14.1 T
Glioma models have provided important insights into human brain cancers. Among the investigative tools, MRI has allowed their characterization and diagnosis. In this study, we investigated whether diffusion MRI might be a useful technique for early detection and characterization of slow-growing and diffuse infiltrative gliomas, such as the proposed new models, LN-2669GS and LN-2540GS glioma sphere xenografts. Tumours grown in these models are not visible in conventional T2-weighted or contrast-enhanced T1-weighted MRI at 14.1 T. Diffusion-weighted imaging and diffusion tensor imaging protocols were optimized for contrast by exploring long diffusion times sensitive for probing the microstructural alterations induced in the normal brain by the slow infiltration of glioma sphere cells. Compared with T2-weighted images, tumours were properly identified in their early stage of growth using diffusion MRI, and confirmed by localized proton MR spectroscopy as well as immunohistochemistry. The first evidence of tumour presence was revealed for both glioma sphere xenograft models three months after tumour implantation, while no necrosis, oedema or haemorrhage were detected either by MRI or by histology. Moreover, different values of diffusion indices, such as mean diffusivity and fractional anisotropy, were obtained in tumours grown from LN-2669GS and LN-2540GS glioma sphere lines. These observations highlighted diverse tumour microstructures for both xenograft models, which were reflected in histology. This study demonstrates the ability of diffusion MRI techniques to identify and investigate early stages of slow-growing, invasive tumours in the mouse brain, thus providing a potential imaging biomarker for early detection of tumours in humans.
NMR in Biomedicine
DOI : 10.1002/nbm.3610
Motion Correction in Magnetic Resonance Imaging Using the Signal of Free-Induction-Decay
Magnetic resonance imaging (MRI) is highly susceptible to subject's motion and can significantly degrade image quality. In brain MRI exams, involuntary head movements can affect the sampled k-space data. Such unintended alterations may result in visible image artifacts such as blurring, ghosting and others, and therefore potentially disqualify the image from diagnostic purposes. Methods to characterize motion in order to mitigate its impact on image quality exist and range from MR sequence based techniques to scanner independent tracking systems. Although, many motion detection and correction strategies have been proposed in the past, a universal solution to the problem does not exist yet. The work of this thesis was focused on the exploitation of the motion information from a multi-channel Free Induction Decay Navigator (FID) to develop and to optimize motion detection and correction methods in structural brain MRI. After a short introduction to the motion problem in MRI the fundamental methodology behind FID based motion detection is presented and used in this thesis. Considerable work has already been done in the field of motion correction for MRI that is summarized by reviewing the most recent literature, which allowed to reveal some pitfalls in the present approaches and to demonstrate the motivation behind an FID-based method for motion correction in MRI. The first study was conducted to demonstrate that substantial motion information is contained in the multi-channel FID signal, whereby the FID signal is correlated with motion parameters that were obtained from a highly accurate optical tracking system. This work was able to confirm the theoretical foundations from the Biot-Savart law, however, also revealed that a pure FID-based method is not sufficient to exactly calculate the underlying motion trajectory. It is speculated that scanner and subject related information might lead to a closed form solution, yet it was not possible to derive one due to a high dimensionality of the motion problem. Therefore, two alternative approaches were developed to utilize the FID signal for motion detection and correction in MRI. First, a prospective motion correction strategy for an MP-RAGE sequence is demonstrated, whereby the FID signal is used to trigger a prospective motion correction mechanism. The second alternative approach describes how the FID signal can be used to evaluate the quality of an already acquired image and how the FID signal can be used as an optimizer for an autofocusing based retrospective motion correction technique.Lausanne, EPFL, 2016.
DOI : 10.5075/epfl-thesis-6963.
Refined Analysis of Brain Energy Metabolism Using In Vivo Dynamic Enrichment of 13C Multiplets
Carbon-13 nuclear magnetic resonance spectroscopy in combination with the infusion of (13)C-labeled precursors is a unique approach to study in vivo brain energy metabolism. Incorporating the maximum information available from in vivo localized (13)C spectra is of importance to get broader knowledge on cerebral metabolic pathways. Metabolic rates can be quantitatively determined from the rate of (13)C incorporation into amino acid neurotransmitters such as glutamate and glutamine using suitable mathematical models. The time course of multiplets arising from (13)C-(13)C coupling between adjacent carbon atoms was expected to provide additional information for metabolic modeling leading to potential improvements in the estimation of metabolic parameters.The aim of the present study was to extend two-compartment neuronal/glial modeling to include dynamics of (13)C isotopomers available from fine structure multiplets in (13)C spectra of glutamate and glutamine measured in vivo in rats brain at 14.1 T, termed bonded cumomer approach. Incorporating the labeling time courses of (13)C multiplets of glutamate and glutamine resulted in elevated precision of the estimated fluxes in rat brain as well as reduced correlations between them.
DOI : 10.1177/1759091416632342
Genetic Polymorphism Associated Prefrontal Glutathione and Its Coupling With Brain Glutamate and Peripheral Redox Status in Early Psychosis
BACKGROUND: Oxidative stress and glutathione (GSH) metabolism dysregulation has been implicated in the pathophysiology of schizophrenia. GAG-trinucleotide repeat (TNR) polymorphisms in the glutamate-cysteine ligase catalytic gene (GCLC), the rate-limiting enzyme for GSH synthesis, are associated with schizophrenia. In addition, GSH may serve as a reserve pool for neuronal glutamate (Glu) through the gamma-glutamyl cycle. The aim of this study is to investigate brain [GSH] and its association with GCLC polymorphism, peripheral redox indices and brain Glu. METHODS: Magnetic resonance spectroscopy was used to measure [GSH] and [Glu] in the medial prefrontal cortex (mPFC) of 25 early-psychosis patients and 33 controls. GCLC polymorphism was genotyped, glutathione peroxidases (GPx) and glutathione reductase (GR) activities were determined in blood cells. RESULTS: Significantly lower [GSHmPFC] in GCLC high-risk genotype subjects were revealed as compared to low-risk genotype subjects independent of disease status. In male subjects, [GSHmPFC] and blood GPx activities correlate positively in controls (P = .021), but negatively in patients (P = .039). In GCLC low-risk genotypes, [GlumPFC] are lower in patients, while it is not the case for high-risk genotypes. CONCLUSIONS: GCLC high-risk genotypes are associated with low [GSHmPFC], highlighting that GCLC polymorphisms should be considered in pathology studies of cerebral GSH. Low brain GSH levels are related to low peripheral oxidation status in controls but with high oxidation status in patients, pointing to a dysregulated GSH homeostasis in early psychosis patients. GCLC polymorphisms and disease associated correlations between brain GSH and Glu levels may allow patients stratification.
DOI : 10.1093/schbul/sbw038
Simultaneous EEG-fMRI at ultra-high field for the study of human brain function
Scalp electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) have highly complementary domains, and their combination has been actively sought within neuroscience research. The important gains in fMRI sensitivity achieved with higher field strengths open exciting perspectives for combined EEG-fMRI; however, simultaneous acquisitions are subject to highly undesirable interactions between the two modalities, which can strongly compromise data quality and subject safety, and most of these interactions are increased at higher fields. The work described in this thesis was centered on the development of simultaneous EEG-fMRI in humans at 7T, covering aspects of subject safety, signal quality assessment, and quality improvement. Additionally, given the potential value of high-field EEG-fMRI to study the neuronal correlates of so-called negative BOLD responses, an initial fMRI study was dedicated to these phenomena. The initial fMRI study aimed to characterize positive (PBR) and negative BOLD responses (NBR) to visual checkerboard stimulation of varying contrast and duration, focusing on NBRs occurring in visual and in auditory cortical regions. Results showed that visual PBRs and both visual and auditory NBRs significantly depend on stimulus contrast and duration, suggesting a dynamic system of visual-auditory interactions, sensitive to stimulus contrast and duration. The neuronal correlates of these interactions could not be addressed in higher detail with fMRI alone, yet could potentially be clarified in future work with combined EEG-fMRI. Moving on to simultaneous EEG-fMRI implementation, the first stage comprised an assessment of potential safety concerns at 7T. The safety tests comprised numerical simulations of RF power distribution and real temperature measurements on a phantom during acquisition. Overall, no significant safety concerns were found for the setup tested. A characterization of artifacts induced on MRI data due to the presence of EEG components was then performed. With the introduction of the EEG system, functional and anatomical images exhibited general losses in spatial SNR, with a smaller loss in temporal SNR in fMRI data. B0 and B1 field mapping pointed towards RF pulse disruption as the major degradation mechanism affecting MRI data. The main part of this work focused on EEG artifacts induced by MRI. The first step focused on optimizing signal transmission between the EEG cap and amplifiers, to minimize artifact contamination at this important stage. Along this line, adequate cable shortening and bundling effectively reduced environment noise in EEG recordings. Simultaneous acquisitions were then performed on humans using the optimized setup. On average, EEG data exhibited clear alpha modulation and average visual evoked potentials (VEP), with concomitant BOLD signal changes. In the second step, a novel approach for head motion artifact detection was developed, based on a simple modification of the EEG cap, and simultaneous acquisitions were performed in volunteers undergoing visual checkerboard stimulation. After gradient artifact correction, EEG signal variance was found to be largely dominated by pulse artifacts, but contributions from spontaneous motion were still comparable to those of neuronal activity. Using a combination of pulse artifact correction, motion artifact correction and ICA denoising, strong improvements in data quality could be obtained, especially at a single-trial level.Lausanne, EPFL, 2016.
DOI : 10.5075/epfl-thesis-6969.
3D T 2-weighted imaging at 7T using dynamic kT-points on single-transmit MRI systems
OBJECTIVES: For turbo spin echo (TSE) sequences to be useful at ultra-high field, they should ideally employ an RF pulse train compensated for the B 1 inhomogeneity. Previously, it was shown that a single kT-point pulse designed in the small tip-angle regime can replace all the pulses of the sequence (static kT-points). This work demonstrates that the B 1 dependence of T 2-weighted imaging can be further mitigated by designing a specific kT-point pulse for each pulse of a 3D TSE sequence (dynamic kT-points) even on single-channel transmit systems MATERIALS AND METHODS: By combining the spatially resolved extended phase graph formalism (which calculates the echo signals throughout the sequence) with a gradient descent algorithm, dynamic kT-points were optimized such that the difference between the simulated signal and a target was minimized at each echo. Dynamic kT-points were inserted into the TSE sequence to acquire in vivo images at 7T. RESULTS: The improvement provided by the dynamic kT-points over the static kT-point design and conventional hard pulses was demonstrated via simulations. Images acquired with dynamic kT-points showed systematic improvement of signal and contrast at 7T over regular TSE-especially in cerebellar and temporal lobe regions without the need of parallel transmission. CONCLUSION: Designing dynamic kT-points for a 3D TSE sequence allows the acquisition of T 2-weighted brain images on a single-transmit system at ultra-high field with reduced dropout and only mild residual effects due to the B 1 inhomogeneity.
Magma (New York, N.Y.)
DOI : 10.1007/s10334-016-0545-4
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.
Journal of Cerebral Blood Flow & Metabolism
DOI : 10.1177/0271678X16629482
Simultaneous and interleaved acquisition of NMR signals from different nuclei with a clinical MRI scanner
PURPOSE: Modification of a clinical MRI scanner to enable simultaneous or rapid interleaved acquisition of signals from two different nuclei. METHODS: A device was developed to modify the local oscillator signal fed to the receive channel(s) of an MRI console. This enables external modification of the frequency at which the receiver is sensitive and rapid switching between different frequencies. Use of the device was demonstrated with interleaved and simultaneous 31 P and 1 H spectroscopic acquisitions, and with interleaved 31 P and 1 H imaging. RESULTS: Signal amplitudes and signal-to-noise ratios were found to be unchanged for the modified system, compared with data acquired with the MRI system in the standard configuration. CONCLUSION: Interleaved and simultaneous 1 H and 31 P signal acquisition was successfully demonstrated with a clinical MRI scanner, with only minor modification of the RF architecture. While demonstrated with 31 P, the modification is applicable to any detectable nucleus without further modification, enabling a wide range of simultaneous and interleaved experiments to be performed within a clinical setting.
Magnetic resonance in medicine
DOI : 10.1002/mrm.26056
Glutathione deficit affects the integrity and function of the fimbria/fornix and anterior commissure in mice: relevance for schizophrenia
BACKGROUND: Structural anomalies of white matter (WM) are found in various brain regions of patients with schizophrenia, bipolar and other psychiatric disorders, but the causes at cellular and molecular levels remain unclear. Oxidative stress and redox dysregulation have been proposed to play a role in the pathophysiology of several psychiatric conditions, but their anatomical and functional consequences are poorly understood. The aim of this study was to investigate WM throughout the brain in a pre-clinical model of redox dysregulation. METHODS: In a mouse model with impaired glutathione synthesis (Gclm KO), a state-of-the-art multimodal magnetic resonance protocol at high field (14.1 T) was used to assess longitudinally the WM structure, prefrontal neurochemical profile and ventricular volume. Electrophysiological recordings in the abnormal WM tracts identified by DTI were performed to characterize the functional consequences of fractional anisotropy (FA) alterations. RESULTS: Structural alterations observed at peri-pubertal age and adulthood in Gclm KO mice were restricted to the anterior commissure (AC) and fornix-fimbria (FF). Reduced FA in the AC (-7.5% /-1.9, p<0.01) and FF (-4.5% /-1.3, p<0.05) were accompanied by reduced conduction velocity in fast-conducting fibers of the posterior limb of the AC (-14.3% /-5.1, p<0.05) and slow-conducting fibers of the FF (-8.6% /-2.6, p<0.05). Ventricular enlargement was found at peri-puberty ( 25% /-8 p<0.05) but not in adult Gclm KO mice. CONCLUSIONS: Glutathione deficit in Gclm KO mice affects ventricular size and the integrity of the FF and AC. This suggests that redox dysregulation could contribute during neurodevelopment to the impaired WM and ventricle enlargement observed in schizophrenia and other psychiatric disorders.
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)
DOI : 10.1093/ijnp/pyv110
Hyperpolarized 6Li as a probe for hemoglobin oxygenation level
Hyperpolarization by dissolution dynamic nuclear polarization (DNP) is a versatile technique to dramatically enhance the nuclear magnetic resonance (NMR) signal intensity of insensitive long-T1 nuclear spins such as 6 Li. The 6 Li longitudinal relaxation of lithium ions in aqueous solutions strongly depends on the concentration of paramagnetic species, even if they are present in minute amounts. We herein demonstrate that blood oxygenation can be readily detected by taking advantage of the 6 Li signal enhancement provided by dissolution DNP, together with the more than 10% decrease in 6 Li longitudinal relaxation as a consequence of the presence of paramagnetic deoxyhemoglobin.
Contrast Media and Molecular Imaging
DOI : 10.1002/cmmi.1656
Three-dimensional echo planar imaging with controlled aliasing: A sequence for high temporal resolution functional MRI
Purpose In this work, we combine three-dimensional echo planar imaging (3D-EPI) with controlled aliasing to substantially increase temporal resolution in whole-brain functional MRI (fMRI) while minimizing geometry-factor (g-factor) losses. Theory and Methods The study was performed on a 7 Tesla scanner equipped with a 32-channel receive coil. The proposed 3D-EPI-CAIPI sequence was evaluated for: (i) image quality, compared with a conventionally undersampled parallel imaging acquisition; (ii) temporal resolution, the ability to sample and remove physiological signal fluctuations from the fMRI signal of interest and (iii) the ability to distinguish small changes in hemodynamic responses in an event-related fMRI experiment. Results Whole-brain fMRI data with a voxel size of 2 × 2 × 2 mm3 and temporal resolution of 371 ms could be acquired with acceptable image quality. Ten-fold parallel imaging accelerated 3D-EPI-CAIPI data were shown to lower the maximum g-factor losses up to 62% with respect to a 10-fold accelerated 3D-EPI dataset. FMRI with 400 ms temporal resolution allowed the detection of time-to-peak variations in functional responses due to multisensory facilitation in temporal, occipital and frontal cortices. Conclusion 3D-EPI-CAIPI allows increased temporal resolution that enables better characterization of physiological noise, thus improving sensitivity to signal changes of interest. Furthermore, subtle changes in hemodynamic response dynamics can be studied in shorter scan times by avoiding the need for jittering.
Magnetic Resonance in Medicine
DOI : 10.1002/mrm.25835
Retrospective correction of involuntary microscopic head movement using highly accelerated fat image navigators (3D FatNavs) at 7T
PURPOSE: The goal of the present study was to use a three-dimensional (3D) gradient echo volume in combination with a fat-selective excitation as a 3D motion navigator (3D FatNav) for retrospective correction of microscopic head motion during high-resolution 3D structural scans of extended duration. The fat excitation leads to a 3D image that is itself sparse, allowing high parallel imaging acceleration factors - with the additional advantage of a minimal disturbance of the water signal used for the host sequence. METHODS: A 3D FatNav was inserted into two structural protocols: an inversion-prepared gradient echo at 0.33 x 0.33 x 1.00 mm resolution and a turbo spin echo at 600 mum isotropic resolution. RESULTS: Motion estimation was possible with high precision, allowing retrospective motion correction to yield clear improvements in image quality, especially in the conspicuity of very small blood vessels. CONCLUSION: The highly accelerated 3D FatNav allowed motion correction with noticeable improvements in image quality, even for head motion which was small compared with the voxel dimensions of the host sequence.
Magnetic Resonance in Medicine
DOI : 10.1002/mrm.25670
Quantitative activity-induced manganese-dependent MRI for characterizing cortical layers in the primary somatosensory cortex of the rat
The ability of Mn2 to follow Ca2 pathways upon stimulation transform them into remarkable surrogate markers of neuronal activity using activity-induced manganese-dependent MRI (AIM–MRI). In the present study, a precise follow-up of physiological parameters during MnCl2 and mannitol infusions improved the reproducibility of AIM–MRI allowing in-depth evaluation of the technique. Pixel-by-pixel T1 data were investigated using histogram distributions in the barrel cortex (BC) and the thalamus before and after Mn2 infusion, after blood brain barrier opening and after BC activation. Mean BC T1 values dropped significantly upon trigeminal nerve (TGN) stimulation (−38 %, P = 0.02) in accordance with previous literature findings. T1 histogram distributions showed that 34 % of T1s in the range 600–1500 ms after Mn2 mannitol infusions shifted to 50–350 ms after TGN stimulation corresponding to a twofold increase of the percentage of pixels with the lowest T1s in BC. Moreover, T1 changes in response to stimulation increased significantly from superficial cortical layers (I–III) to deeper layers (V–VI). Cortical cytoarchitecture detection during a functional paradigm was performed extending the potential of AIM–MRI. Quantitative AIM–MRI could thus offer a means to interpret local neural activity across cortical layers while identification of the role of calcium dynamics in vivo during brain activation could play a key role in resolving neurovascular coupling mechanisms.
Brain Structure and Function
DOI : 10.1007/s00429-014-0933-3
Fasting-induced changes of hepatic lipid and carbohydrate stores in the absence of GLUT22015. 40th Congress of the Federation-of-European-Biochemical-Societies (FEBS) - The Biochemical Basis of Life , Berlin, GERMANY , JUL 04-09, 2015. p. 229-229.
GDH-Dependent Glutamate Oxidation in the Brain Dictates Peripheral Energy Substrate Distribution
Glucose, the main energy substrate used in the CNS, is continuously supplied by the periphery. Glutamate, the major excitatory neurotransmitter, is foreseen as a complementary energy contributor in the brain. In particular, astrocytes actively take up glutamate and may use it through oxidative glutamate dehydrogenase (GDH) activity. Here, we investigated the significance of glutamate as energy substrate for the brain. Upon glutamate exposure, astrocytes generated ATP in a GDH-dependent way. The observed lack of glutamate oxidation in brain-specific GDH null CnsGlud1−/− mice resulted in a central energy-deprivation state with increased ADP/ATP ratios and phospho-AMPK in the hypothalamus. This induced changes in the autonomous nervous system balance, with increased sympathetic activity promoting hepatic glucose production and mobilization of substrates reshaping peripheral energy stores. Our data reveal the importance of glutamate as necessary energy substrate for the brain and the role of central GDH in the regulation of whole-body energy homeostasis.
DOI : 10.1016/j.celrep.2015.09.003
Noninvasive assessment of presymptomatic and symptomatic metabolic changes in the brain and brainstem of an ALS mouse model2015. 25th Biennial Meeting of the International-Society-for-Neurochemistry Jointly with the 13th Meeting of the Asian-Pacific-Society-for-Neurochemistry in Conjunction with the 35th Meeting of the Australasian-Neuroscience-Society , Cairns, AUSTRALIA , AUG 23-27, 2015. p. 339-340.
Energy metabolism in the rat cortex under deep thiopental anesthesia measured in vivo by 13C MRS at 14.1 T2015. 25th Biennial Meeting of the International-Society-for-Neurochemistry Jointly with the 13th Meeting of the Asian-Pacific-Society-for-Neurochemistry in Conjunction with the 35th Meeting of the Australasian-Neuroscience-Society , Cairns, AUSTRALIA , AUG 23-27, 2015. p. 264-265.
Correcting surface coil excitation inhomogeneities in single-shot SPEN MRI
Given their high sensitivity and ability to limit the field of view (FOV), surface coils are often used in magnetic resonance spectroscopy (MRS) and imaging (MRI). A major downside of surface coils is their inherent radiofrequency (RF) B1 heterogeneity across the FOV, decreasing with increasing distance from the coil and giving rise to image distortions due to non-uniform spatial responses. A robust way to compensate for B1 inhomogeneities is to employ adiabatic inversion pulses, yet these are not well adapted to all imaging sequences –including to single-shot approaches like echo planar imaging (EPI). Hybrid spatiotemporal encoding (SPEN) sequences relying on frequency-swept pulses provide another ultrafast MRI alternative, that could help solve this problem thanks to their built-in heterogeneous spatial manipulations. This study explores how this intrinsic SPEN-based spatial discrimination, could be used to compensate for the B1 inhomogeneities inherent to surface coils. Experiments carried out in both phantoms and in vivo rat brains demonstrate that, by suitably modulating the amplitude of a SPEN chirp pulse that progressively excites the spins in a direction normal to the coil, it is possible to compensate for the RF transmit inhomogeneities and thus improve sensitivity and image fidelity.
Journal of Magnetic Resonance
DOI : 10.1016/j.jmr.2015.08.018
In Vivo Longitudinal (1)H MRS Study of Transgenic Mouse Models of Prion Disease in the Hippocampus and Cerebellum at 14.1 T
In vivo (1)H MR spectroscopy allows the non invasive characterization of brain metabolites and it has been used for studying brain metabolic changes in a wide range of neurodegenerative diseases. The prion diseases form a group of fatal neurodegenerative diseases, also described as transmissible spongiform encephalopathies. The mechanism by which prions elicit brain damage remains unclear and therefore different transgenic mouse models of prion disease were created. We performed an in vivo longitudinal (1)H MR spectroscopy study at 14.1 T with the aim to measure the neurochemical profile of Prnp -/- and PrPΔ32-121 mice in the hippocampus and cerebellum. Using high-field MR spectroscopy we were able to analyze in details the in vivo brain metabolites in Prnp -/- and PrPΔ32-121 mice. An increase of myo-inositol, glutamate and lactate concentrations with a decrease of N-acetylaspartate concentrations were observed providing additional information to the previous measurements.
DOI : 10.1007/s11064-015-1643-9
Stroking or Buzzing? A Comparison of Somatosensory Touch Stimuli Using 7 Tesla fMRI
Studying body representations in the brain helps us to understand how we humans relate to our own bodies. The in vivo mapping of the somatosensory cortex, where these representations are found, is greatly facilitated by the high spatial resolution and high sensitivity to brain activation available at ultra-high field. In this study, the use of different stimulus types for somatotopic mapping of the digits at ultra-high field, specifically manual stroking and mechanical stimulation, was compared in terms of sensitivity and specificity of the brain responses. Larger positive responses in digit regions of interest were found for manual stroking than for mechanical stimulation, both in terms of average and maximum t-value and in terms of number of voxels with significant responses to the tactile stimulation. Responses to manual stroking were higher throughout the entire post-central sulcus, but the difference was especially large on its posterior wall, i.e. in Brodmann area 2. During mechanical stimulation, cross-digit responses were more negative than during manual stroking, possibly caused by a faster habituation to the stimulus. These differences indicate that manual stroking is a highly suitable stimulus for fast somatotopic mapping procedures, especially if Brodmann area 2 is of interest.
DOI : 10.1371/journal.pone.0134610
Direct noninvasive estimation of myocardial tricarboxylic acid cycle flux in vivo using hyperpolarized 13C 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 13C 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 [1-13C]acetate was administered at different concentrations in healthy rats. 13C incorporation into [1-13C]acetylcarnitine and the TCA cycle intermediate [5-13C]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 13C labeling in acetate, acetylcarnitine, and citrate. VTCA was estimated to be 6.7 /-1.7mumol.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 13C signal evolution of citrate, i.e. citrate formation was independent of the amount of injected acetate, while the 13C signal evolution of acetylcarnitine revealed a dose dependency with the injected acetate. The 13C 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 [1-13C]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 13C labeling of acetylcarnitine. Dynamic 13C MRS coupled to the injection of hyperpolarized [1-13C]acetate can enable the measurement of metabolic changes during impaired heart function.
Journal of Molecular and Cellular Cardiology
DOI : 10.1016/j.yjmcc.2015.08.012
Towards high-quality simultaneous EEG-fMRI at 7T: Detection and reduction of EEG artifacts due to head motion
The enhanced functional sensitivity offered by ultra-high field imaging may significantly benefit simultaneous EEG-fMRI studies, but the concurrent increases in artifact contamination can strongly compromise EEG data quality. In the present study, we focus on EEG artifacts created by head motion in the static B0 field. A novel approach for motion artifact detection is proposed, based on a simple modification of a commercial EEG cap, in which four electrodes are non-permanently adapted to record only magnetic induction effects. Simultaneous EEG-fMRI data were acquired with this setup, at 7 T, from healthy volunteers undergoing a reversing-checkerboard visual stimulation paradigm. Data analysis assisted by the motion sensors revealed that, after gradient artifact correction, EEG signal variance was largely dominated by pulse artifacts (81–93%), but contributions from spontaneous motion (4–13%) were still comparable to or even larger than those of actual neuronal activity (3–9%). Multiple approaches were tested to determine the most effective procedure for denoising EEG data incorporating motion sensor information. Optimal results were obtained by applying an initial pulse artifact correction step (AAS-based), followed by motion artifact correction (based on the motion sensors) and ICA denoising. On average, motion artifact correction (after AAS) yielded a 61% reduction in signal power and a 62% increase in VEP trial-by-trial consistency. Combined with ICA, these improvements rose to a 74% power reduction and an 86% increase in trial consistency. Overall, the improvements achieved were well appreciable at single-subject and single-trial levels, and set an encouraging quality mark for simultaneous EEG-fMRI at ultra-high field.
DOI : 10.1016/j.neuroimage.2015.07.020
Characterization of hepatic fatty acids in mice with reduced liver fat by ultra-short echo time (1) H-MRS at 14.1 T in vivo
Alterations in the hepatic lipid content (HLC) and fatty acid composition are associated with disruptions in whole body metabolism, both in humans and in rodent models, and can be non-invasively assessed by (1) H-MRS in vivo. We used (1) H-MRS to characterize the hepatic fatty-acyl chains of healthy mice and to follow changes caused by streptozotocin (STZ) injection. Using STEAM at 14.1 T with an ultra-short TE of 2.8 ms, confounding effects from T2 relaxation and J-coupling were avoided, allowing for accurate estimations of the contribution of unsaturated (UFA), saturated (SFA), mono-unsaturated (MUFA) and poly-unsaturated (PUFA) fatty-acyl chains, number of double bonds, PU bonds and mean chain length. Compared with in vivo (1) H-MRS, high resolution NMR performed in vitro in hepatic lipid extracts reported longer fatty-acyl chains (18 versus 15 carbons) with a lower contribution from UFA (61 ± 1% versus 80 ± 5%) but a higher number of PU bonds per UFA (1.39 ± 0.03 versus 0.58 ± 0.08), driven by the presence of membrane species in the extracts. STZ injection caused a decrease of HLC (from 1.7 ± 0.3% to 0.7 ± 0.1%), an increase in the contribution of SFA (from 21 ± 2% to 45 ± 6%) and a reduction of the mean length (from 15 to 13 carbons) of cytosolic fatty-acyl chains. In addition, SFAs were also likely to have increased in membrane lipids of STZ-induced diabetic mice, along with a decrease of the mean chain length. These studies show the applicability of (1) H-MRS in vivo to monitor changes in the composition of the hepatic fatty-acyl chains in mice even when they exhibit reduced HLC, pointing to the value of this methodology to evaluate lipid-lowering interventions in the scope of metabolic disorders. Copyright © 2015 John Wiley & Sons, Ltd.
NMR in biomedicine
DOI : 10.1002/nbm.3345
Radical-free mixture of co-polarized 13C metabolites for probing separate biochemical pathways in vivo by hyperpolarized 13C MR2015. International Society for Magnetic Resonance in Medicine , Toronto , June, 2015. p. 416.
Metabolic flux analysis of hepatic mitochondrial oxidation of hyperpolarized [1-13C] and [2-13C] pyruvate in vivo2015. International Society for Magnetic Resonance in Medicine , Toronto , June, 2015. p. 327.
Evidence From Imaging Studies For Oxidative Stress Mechanisms In First Episode Schizophrenia2015. 15th International Congress on Schizophrenia Research (ICOSR) , Colorado Springs, CO , MAR 28-APR 01, 2015. p. S253-S253.
Physiological noise in human cerebellar fMRI
Objectives To compare physiological noise contributions in cerebellar and cerebral regions of interest in high-resolution functional magnetic resonance imaging (fMRI) data acquired at 7T, to estimate the need for physiological noise removal in cerebellar fMRI. Materials and methods Signal fluctuations in high resolution (1 mm isotropic) 7T fMRI data were attributed to one of the following categories: task-induced BOLD changes, slow drift, signal changes correlated with the cardiac and respiratory cycles, signal changes related to the cardiac rate and respiratory volume per unit of time or other. R2adj values for all categories were compared across regions of interest. Results In this high-resolution data, signal fluctuations related to the phase of the cardiac cycle and cardiac rate were shown to be significant, but comparable between cerebellar and cerebral regions of interest. However, respiratory related signal fluctuations were increased in the cerebellar regions, with explained variances that were up to 80 % higher than for the primary motor cortex region. Conclusion Even at a millimetre spatial resolution, significant correlations with both cardiac and respiratory RETROICOR components were found in all healthy volunteer data. Therefore, physiological noise correction is highly likely to improve the temporal signal-to-noise ratio (SNR) for cerebellar fMRI at 7T, even at high spatial resolution.
Magnetic Resonance Materials in Physics, Biology and Medicine
DOI : 10.1007/s10334-015-0483-6
B1 -mapping and B1 inhomogeneity correction at high field
Magnetic resonance images acquired at the highest strength of the main magnetic field B0 are of interest since they highly benefit from an increased signal to noise ratio. At ultra high field strengths (B0 > 7 Tesla) images with more contrast and higher resolution can thus be obtained, opening new insights into the understanding of organ structures and disease evolutions. One of the main challenges of ultra high field MR imaging is that the wavelength of MR radiations starts to be shorter than the typical organs of interest. At such wavelength, the transmit magnetic field B1 used to manipulate the magnetization in MR imaging is subject to constructive and destructive interferences and becomes position dependent. This inhomogeneity in the B1 field leads to signal and contrast variations in the anatomical images which are prone to misinterpretation. This thesis is about measuring and correcting the inhomogeneous B1 field at 7 Tesla. To be able to correct the B1 inhomogeneity, it is necessary to measure it first. An appropriate B1 -mapping sequence should provide accurate measurements in a wide range of B1 values in a short amount of time since the acquisition of the B1 distribution can be considered as an adjustment step. The SA2RAGE sequence was developed according to these criteria, allowing a typical three-dimensional B1 map to be acquired in less than 2min. The next challenge was to correct the B1 inhomogeneity observed across the brain at 7 Tesla. To obtain results of high quality, RF pulses were designed to generate the desired magnetization profile. It was already known that kT-point pulses designed in the small tip angle (STA) approximation provided substantial B1 inhomogeneity correction. In this thesis, a methodology expressing the Bloch equations in a linear form was developed for the design of kT-point pulses beyond the STA regime. Excitation, inversion and refocusing pulses were designed and significant improvements were observed in the associated magnetization profiles when compared to the results found in the STA regime. The last part of the thesis was dedicated to the design of kT-points for a turbo spin echo (TSE) sequence in order to remove the effect of the B1 inhomogeneity on T2-weighted imaging at 7 Tesla. In the first approach, a kT-point pulse was designed in the STA regime to make the excitation profile as homogeneous as possible. It was demonstrated that a symmetric kT-point pulse designed in the STA regime still generates an homogeneous excitation profile for flip angles as high as 120°. A unique symmetric kT-point pulse was designed in the STA regime and used to replace all the original hard pulses of a TSE sequence (static design). By adding parallel transmission, anatomical images largely devoid of artifacts resulting from the common B1 inhomogeneity at 7 Tesla were acquired. To be able to acquire T2-weighted images with signal and contrast homogeneity by using a more efficient TSE sequence protocol, a specific kT-point waveform was optimized for each pulse of the TSE sequence (dynamic design). It was demonstrated that, although at a cost of an increase of the specific absorption rate, the dynamic outperforms the static kT-point design in terms of signal and contrast homogeneity obtained in the acquired T2-weighted images. The use of dynamic kT-points to obtain such a quality in T2-weighted imaging is thus promising for clinical applications at ultra high field.Lausanne, EPFL, 2015.
DOI : 10.5075/epfl-thesis-6582.
Distinct contributions of Brodmann areas 1 and 2 to body ownership
Although body ownership – i.e. the feeling that our bodies belong to us – modulates activity within the primary somatosensory cortex (S1), it is still unknown whether this modulation occurs within a somatotopically defined portion of S1. We induced an illusory feeling of ownership for another person's finger by asking participants to hold their palm against another person's palm and to stroke the two joined index fingers with the index and thumb of their other hand. This illusion (numbness illusion) does not occur if the stroking is performed by the other person. We combined this somatosensory paradigm with ultra-high field fMRI finger mapping to study whether illusory body ownership modulates activity within different finger-specific areas of S1. The results revealed that the numbness illusion is associated with activity in Broadman area (BA) 1 within the representation of the finger stroking the other person's finger and in BA 2 contralateral to the stroked finger. These results show that changes in bodily experience modulate the activity within certain subregions of S1, with a different topographical selectivity between the representations of the stroking and of the stroked hand, and reveal that the high degree of somatosensory specialization in S1 extends to bodily self-consciousness.
Social Cognitive and Affective Neuroscience
DOI : 10.1093/scan/nsv031
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 © 2015 John Wiley & Sons, Ltd.
NMR in biomedicine
DOI : 10.1002/nbm.3263
Assessment of metabolic fluxes in the mouse brain in vivo using (1)H-[(13)C] NMR spectroscopy at 14.1 Tesla
(13)C magnetic resonance spectroscopy (MRS) combined with the administration of (13)C labeled substrates uniquely allows to measure metabolic fluxes in vivo in the brain of humans and rats. The extension to mouse models may provide exclusive prospect for the investigation of models of human diseases. In the present study, the short-echo-time (TE) full-sensitivity (1)H-[(13)C] MRS sequence combined with high magnetic field (14.1 T) and infusion of [U-(13)C6] glucose was used to enhance the experimental sensitivity in vivo in the mouse brain and the (13)C turnover curves of glutamate C4, glutamine C4, glutamate glutamine C3, aspartate C2, lactate C3, alanine C3, γ-aminobutyric acid C2, C3 and C4 were obtained. A one-compartment model was used to fit (13)C turnover curves and resulted in values of metabolic fluxes including the tricarboxylic acid (TCA) cycle flux VTCA (1.05±0.04 μmol/g per minute), the exchange flux between 2-oxoglutarate and glutamate Vx (0.48±0.02 μmol/g per minute), the glutamate-glutamine exchange rate Vgln (0.20±0.02 μmol/g per minute), the pyruvate dilution factor Kdil (0.82±0.01), and the ratio for the lactate conversion rate and the alanine conversion rate VLac/VAla (10±2). This study opens the prospect of studying transgenic mouse models of brain pathologies.Journal of Cerebral Blood Flow & Metabolism advance online publication, 21 January 2015; doi:10.1038/jcbfm.2014.251.
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
DOI : 10.1038/jcbfm.2014.251
Improved surface coil design and pulse sequence development for in vivo 13C MR spectroscopy of humans at 7T
Nuclear magnetic resonance (NMR) is a non-invasive tool for the study of human diseases. In particular, carbon-13 magnetic resonance spectroscopy (13C MRS) is a promising derivative tool for investigating metabolism in vivo, as it allows the non-invasive measurement of complex molecules in living organs, such as glycogen macromolecule in human muscle. The use of high magnetic field strength benefits the signal-to-noise ratio (SNR) and spectral resolution, at the expense of requiring high transmitted power. As of today, the application of 13C MRS to humans is currently performed at low magnetic field strength (i.e. 3T), while its applications at high field is still limited due to methodological aspects. This thesis focuses in investigating the feasibility 13C MRS into clinical applications at high field (i.e. 7T) by measuring glycogen in human muscle, as a step towards clinical 13C MRS in human brain.Lausanne, EPFL, 2015.
DOI : 10.5075/epfl-thesis-6455.
Brain energy metabolism measured by 13C magnetic resonance spectroscopy in vivo upon infusion of [3-13C]lactate
The brain uses lactate produced by glycolysis as an energy source. How lactate originated from the blood stream is used to fuel brain metabolism is not clear. The current study measures brain metabolic fluxes and estimates the amount of pyruvate that becomes labeled in glial and neuronal compartments upon infusion of [3-13 C]lactate. For that, labeling incorporation into carbons of glutamate and glutamine was measured by 13 C magnetic resonance spectroscopy at 14.1 T and analyzed with a two-compartment model of brain metabolism to estimate rates of mitochondrial oxidation, glial pyruvate carboxylation, and the glutamate-glutamine cycle as well as pyruvate fractional enrichments. Extracerebral lactate at supraphysiological levels contributes at least two-fold more to replenish the neuronal than the glial pyruvate pools. The rates of mitochondrial oxidation in neurons and glia, pyruvate carboxylase, and glutamate-glutamine cycles were similar to those estimated by administration of 13 C-enriched glucose, the main fuel of brain energy metabolism. These results are in agreement with primary utilization of exogenous lactate in neurons rather than astrocytes.
Journal of Neuroscience Research
DOI : 10.1002/jnr.23531
A Modulated Closed Form solution for Quantitative Susceptibility Mapping - A thorough evaluation and comparison to iterative methods based on edge prior knowledge
The aim of this study is to perform a thorough comparison of quantitative susceptibility mapping (QSM) techniques and their dependence on the assumptions made. The compared methodologies were: two iterative single orientation methodologies minimizing the l2, l1TV norm of the prior knowledge of the edges of the object, one over-determined multiple orientation method (COSMOS) and anewly proposed modulated closed-form solution (MCF). The performance of these methods was compared using a numerical phantom and in-vivo high resolution (0.65 mm isotropic) brain data acquired at 7 T using a new coil combination method. For all QSM methods, the relevant regularization and prior-knowledge parameters were systematically changed in order to evaluate the optimal reconstruction in the presence and absence of a ground truth. Additionally, the QSM contrast was compared to conventional gradient recalled echo (GRE) magnitude and R2* maps obtained from the same dataset. The QSM reconstruction results of the single orientation methods show comparable performance. The MCF method has the highest correlation (corrMCF = 0.95, r2MCF = 0.97) with the state of the art method (COSMOS) with additional advantage of extreme fast computation time. The l-curve method gave the visually most satisfactory balance between reduction of streaking artifacts and over-regularization with the latter being overemphasized when the using the COSMOS susceptibility maps as ground-truth. R2* and susceptibility maps, when calculated from the same datasets, although based on distinct features of the data, have a comparable ability to distinguish deep gray matter structures.
DOI : 10.1016/j.neuroimage.2014.11.038
Simultaneous EEG–fMRI at ultra-high field: Artifact prevention and safety assessment
The simultaneous recording of scalp electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) can provide unique insights into the dynamics of human brain function, and the increased functional sensitivity offered by ultra-high field fMRI opens exciting perspectives for the future of this multimodal approach. However, simultaneous recordings are susceptible to various types of artifacts, many of which scale with magnetic field strength and can seriously compromise both EEG and fMRI data quality in recordings above 3 T. The aim of the present study was to implement and characterize an optimized setup for simultaneous EEG–fMRI in humans at 7 T. The effects of EEG cable length and geometry for signal transmission between the cap and amplifiers were assessed in a phantom model, with specific attention to noise contributions from the MR scanner coldheads. Cable shortening (down to 12 cm from cap to amplifiers) and bundling effectively reduced environment noise by up to 84% in average power and 91% in inter-channel power variability. Subject safety was assessed and confirmed via numerical simulations of RF power distribution and temperature measurements on a phantom model, building on the limited existing literature at ultra-high field. MRI data degradation effects due to the EEG system were characterized via B0 and B1 field mapping on a human volunteer, demonstrating important, although not prohibitive, B1 disruption effects. With the optimized setup, simultaneous EEG–fMRI acquisitions were performed on 5 healthy volunteers undergoing two visual paradigms: an eyes-open/eyes-closed task, and a visual evoked potential (VEP) paradigm using reversing-checkerboard stimulation. EEG data exhibited clear occipital alpha modulation and average VEPs, respectively, with concomitant BOLD signal changes. On a single-trial level, alpha power variations could be observed with relative confidence on all trials; VEP detection was more limited, although statistically significant responses could be detected in more than 50% of trials for every subject. Overall, we conclude that the proposed setup is well suited for simultaneous EEG–fMRI at 7 T.
DOI : 10.1016/j.neuroimage.2014.10.055
Single acquisition electrical property mapping based on relative coil sensitivities: A proof-of-concept demonstration
All methods presented to date to map both conductivity and permittivity rely on multiple acquisitions to compute quantitatively the magnitude of radiofrequency transmit fields, B1 . In this work, we propose a method to compute both conductivity and permittivity based solely on relative receive coil sensitivities ( B1-) that can be obtained in one single measurement without the need to neither explicitly perform transmit/receive phase separation nor make assumptions regarding those phases.
Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine
DOI : 10.1002/mrm.25399
Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients
Schizophrenia pathophysiology implies both abnormal redox control and dysconnectivity of the prefrontal cortex, partly related to oligodendrocyte and myelin impairments. As oligodendrocytes are highly vulnerable to altered redox state, we investigated the interplay between glutathione and myelin. In control subjects, multimodal brain imaging revealed a positive association between medial prefrontal glutathione levels and both white matter integrity and resting-state functional connectivity along the cingulum bundle. In early psychosis patients, only white matter integrity was correlated with glutathione levels. On the other side, in the prefrontal cortex of peripubertal mice with genetically impaired glutathione synthesis, mature oligodendrocyte numbers, as well as myelin markers, were decreased. At the molecular levels, under glutathione-deficit conditions induced by short hairpin RNA targeting the key glutathione synthesis enzyme, oligodendrocyte progenitors showed a decreased proliferation mediated by an upregulation of Fyn kinase activity, reversed by either the antioxidant N-acetylcysteine or Fyn kinase inhibitors. In addition, oligodendrocyte maturation was impaired. Interestingly, the regulation of Fyn mRNA and protein expression was also impaired in fibroblasts of patients deficient in glutathione synthesis. Thus, glutathione and redox regulation have a critical role in myelination processes and white matter maturation in the prefrontal cortex of rodent and human, a mechanism potentially disrupted in schizophrenia.
DOI : 10.1038/mp.2014.88
Parallel imaging with phase scrambling
PURPOSE: Most existing methods for accelerated parallel imaging in MRI require additional data, which are used to derive information about the sensitivity profile of each radiofrequency (RF) channel. In this work, a method is presented to avoid the acquisition of separate coil calibration data for accelerated Cartesian trajectories. METHODS: Quadratic phase is imparted to the image to spread the signals in k-space (aka phase scrambling). By rewriting the Fourier transform as a convolution operation, a window can be introduced to the convolved chirp function, allowing a low-resolution image to be reconstructed from phase-scrambled data without prominent aliasing. This image (for each RF channel) can be used to derive coil sensitivities to drive existing parallel imaging techniques. As a proof of concept, the quadratic phase was applied by introducing an offset to the x2 - y2 shim and the data were reconstructed using adapted versions of the image space-based sensitivity encoding and GeneRalized Autocalibrating Partially Parallel Acquisitions algorithms. RESULTS: The method is demonstrated in a phantom (1 x 2, 1 x 3, and 2 x 2 acceleration) and in vivo (2 x 2 acceleration) using a 3D gradient echo acquisition. CONCLUSION: Phase scrambling can be used to perform parallel imaging acceleration without acquisition of separate coil calibration data, demonstrated here for a 3D-Cartesian trajectory. Further research is required to prove the applicability to other 2D and 3D sampling schemes.
Magnetic Resonance in Medicine
DOI : 10.1002/mrm.25252
Fast low-specific absorption rate B0-mapping along projections at high field using two-dimensional radiofrequency pulses
Purpose At 7 Tesla (T), conventional static field (B0) projection mapping techniques, e.g., FASTMAP, FASTESTMAP, lead to elevated specific absorption rates (SAR), requiring longer total acquisition times (TA). In this work, the series of adiabatic pulses needed for slab selection in FASTMAP is replaced by a single two-dimensional radiofrequency (2D-RF) pulse to minimize TA while ensuring equal shimming performance. Methods Spiral gradients and 2D-RF pulses were designed to excite thin slabs in the small tip angle regime. The corresponding selection profile was characterized in phantoms and in vivo. After optimization of the shimming protocol, the spectral linewidths obtained after 2D localized shimming were compared with conventional techniques and published values from (Emir et al NMR Biomed 2012;25:152–160) in six different brain regions. Results Results on healthy volunteers show no significant difference (P > 0.5) between the spectroscopic linewidths obtained with the adiabatic (TA = 4 min) and the new low-SAR and time-efficient FASTMAP sequence (TA = 42 s). The SAR can be reduced by three orders of magnitude and TA accelerated six times without impact on the shimming performances or quality of the resulting spectra. Conclusion Multidimensional pulses can be used to minimize the RF energy and time spent for automated shimming using projection mapping at high field.
Magnetic Resonance in Medicine
DOI : 10.1002/mrm.25217
A double-quadrature radiofrequency coil design for proton-decoupled carbon-13 magnetic resonance spectroscopy in humans at 7T
Purpose Carbon-13 magnetic resonance spectroscopy (13C-MRS) is challenging because of the inherent low sensitivity of 13C detection and the need for radiofrequency transmission at the 1H frequency while receiving the 13C signal, the latter requiring electrical decoupling of the 13C and 1H radiofrequency channels. In this study, we added traps to the 13C coil to construct a quadrature-13C/quadrature-1H surface coil, with sufficient isolation between channels to allow simultaneous operation at both frequencies without compromise in coil performance. Methods Isolation between channels was evaluated on the bench by measuring all coupling parameters. The quadrature mode of the quadrature-13C coil was assessed using in vitro 23Na gradient echo images. The signal-to-noise ratio (SNR) was measured on the glycogen and glucose resonances by 13C-MRS in vitro, compared with that obtained with a linear-13C/quadrature-1H coil, and validated by 13C-MRS in vivo in the human calf at 7T. Results Isolation between channels was better than −30 dB. The 23Na gradient echo images indicate a region where the field is strongly circularly polarized. The quadrature coil provided an SNR enhancement over a linear coil of 1.4, in vitro and in vivo. Conclusion It is feasible to construct a double-quadrature 13C-1H surface coil for proton decoupled sensitivity enhanced 13C-NMR spectroscopy in humans at 7T.
Magnetic Resonance in Medicine
DOI : 10.1002/mrm.25171
Ultra-High Field Birdcage Coils: a Comparison Study at 14.1T
An essential feature of magnetic resonance (MR) probes for magnetic resonance imaging and spectroscopy is the ability to generate uniform B-1( ) excitation in a volume of interest. When the magnetic field strength is increased, leading to an increase in resonance frequency, the constraints on the MR probes size, the sample size and the associated radiation losses caused by conductor elements are higher. In this study we simulate, test and construct two birdcage coils for imaging rodents operated at 14.1 T. Bench experiments and imaging tests show that at 14.1 T dielectric resonance effect is the dominant factor accounting for B-1( ) field inhomogeneity but remained achievable for imaging rodent brains.2014. 36th Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society (EMBC) , Chicago, IL , AUG 26-30, 2014. p. 2360-2363.
FID navigator triggered acquisition of imaging navigators for retrospective head motion correction2014. ISMRM Workshop on Motion Correction , Tromso, Norway , July 11-14, 2014.
Impact of hepatic lipid accumulation and composition on glucose tolerance and insulin sensitivity: a longitudinal study in male and female mice2014. p. S240-S240.
Impact of insulin resistance on memory performance, brain morphology and neurochemical profiles of the cortex and hippocampus2014. p. S276-S277.
1H MRS to investigate the hepatic profile of GLUT2-/- mice
We performed 1H MRS at 14.1T in the liver of GLUT2-/- and wild-type (WT) mice. Improved spectral resolution allowed identifying peaks from the lipid resonances, choline containing compounds, taurine and glycogen in WT mice. Performing the same measurements in GLUT2-/- mice revealed a strong contribution from carbohydrates, notably glucose, to the 1H MR liver spectrum. Also a reduced lipid content was detected by 1H MRS in those mice. The characterization of the hepatic profile by 1H MRS in GLUT2-/- mice is of great value to address changes in the main energy fuels in the liver longitudinally.Joint Annual Meeting ISMRM-ESMRMB, Milan, Italy, 10-16 May 2014.
Neurochemical profile differentiation of glioma induced by cancer stem cells expressing WIF1: a 1H-MRS longitudinal study at 14.1T2014. International Society for Magnetic Resonance in Medicine , Milan , May 10-16, 2014.
In vivo 13C MRS in the mouse brain at 14.1 T and metabolic flux quantification during infusion of [1,6-13C2] Glucose2014. International Society for Magnetic Resonance in Medicine , Milan , May 10-16, 2014.
Impact of hepatic lipid accumulation and composition on glucose tolerance and insulin sensitivity: a longitudinal study in male and female mice
Background and aims: Metabolic disruptions characterized by high hepatic lipid content (HLC) are associated with impairments in whole body glucose homeostasis. To gain insight on the role of hepatic lipids in the metabolic performance in the absence artificial metabolic stresses we measured non- invasively and longitudinally the HLC and profile in mice during adult devel - opment by Magnetic Resonance (MR) Spectroscopy in vivo . In parallel, mice were challenged with insulin and glucose tolerance tests. Materials and methods: Male (N=10) and female (N=10) C57Bl/6J mice were studied at 3 (3Mo), 7 (7Mo) and 10 months (10Mo) of age. Mice were scanned in a 14.1 T magnet with a 1 H quadrature surface coil over the abdo - men. Localized 1 H spectra were acquired from a 8 μl volume with stimulated echo acquisition mode sequence and the HLC expressed as the percent of to - tal 1 H MR signal, with corrections for spin-spin relaxation effects. Additional spectra were acquired from the same volume with suppression of the water signal to enable the detection and quantification of all the lipid protons. The lipid profile was characterized by the following indices: saturated component (SC); unsaturated fatty acyl chains (UFA); mean number of double bonds per fatty acyl chain (ndb/FA), mean number of poly-unsaturated double bonds per fatty acyl chain (PUdb/FA) and per UFA (PUdb/UFA); mean chain length (MCL). OGTTs (1.5 g/Kg) and i.p. insulin tolerance tests (ITTs) were per - formed after a 6h-fast. Plasma insulin was determined by ELISA and insulin sensitivity estimated with the quantitative insulin check index (QUICKI) as the inverse of the log 10 sum of fasting insulin (μIU/ml) and fasting glucose (mg/dl). Data are expressed as mean ± SEM. Statistical significance was ac - cepted for a P < 0.05 (one-way ANOVA with Newman-Keuls post test) and correlations assessed by the Pearson r coefficient. Results: In males, the HLC at 3Mo was 1.35 ± 0.15%, increasing to 3.06 ± 0.38% at 7Mo, not different from 2.70 ± 0.31% at 10Mo. Females had higher HLC at 3Mo (2.63 ± 0.19%) but no further changes henceforward (2.31 ± 0.20% at 7Mo; 2.36 ± 0.20% at10 Mo). In males, the SC and MCL of hepatic lipids increased with age, with a trend for decreased PUdb/FA and PUdb/ UFA with no changes in ndb/FA or UFA content. Females showed the same trends. Glycemia 3h-post ITT and 2h-post OGTT was lower in females, while QUICKI was higer. These scores were preserved until 10Mo in females. In males, glycemia 2-h post OGTT increased with age and the area above the curve (AAC) for the ITT decreased. In males, but not females, higher body weight correlated with hepatic lipid accumulation ( r = 0.7); worse ITT scores correlated with higher body weight ( r = -0.6) and HLC ( r = -0.7) and lower Pudb/UFA ( r = 0.5); worse OGTT scores correlated with higher HLC ( r = 0.4). Conclusion: In male mice, loss of insulin sensitivity correlated with weight gain, HL accumulation and lower poly-unsaturation. Glucose intolerance was specifically associated with HLC, suggesting a deleterious effect of lipids on the adaptation of hepatic metabolism to the fed state. This behaviour was not observed in females even if they showed similar HLC. In fact, the poly- unsaturation of HL in females didn’t change with HLC, suggesting a positive effect of PUFA on preserving the hepatic metabolic performance.2014. 50th EASD Annual Meeting , Vienna, Austria , 15-19 September 2014. p. s1-s564.
DOI : 10.1007/s00125-014-3355-0.
High Temporal Resolution Functional Magnetic Resonance Imaging at 7 Tesla
Speed has always been a critical consideration in magnetic resonance imaging (MRI), promising dramatic gains in imaging speed, a reduction in motion and susceptibility artifacts, and ultimately increased throughput for clinical studies. This thesis presents several new approaches to increase temporal resolution of a three dimensional (3D) echo planar imaging (EPI) sequence and explores the benefits of using high temporal resolution for both event-related brain activation and resting state networks fMRI studies. In the first approach, a new k-space traversal strategy for segmented 3D EPI is introduced which we termed as 3D reduced excitation EPI (3D RE-EPI). In this approach, two partitions are encoded per radio frequency (RF) excitation, effectively reducing the number of excitations used to acquire a 3D EPI dataset by a factor of two. With this strategy, whole-brain images with a nominal voxel size of 2mmisotropic could be acquired with a temporal resolution under half a second, using traditional parallel imaging acceleration upto 4x in the partition-encoding direction and using novel data acquisition speed-up of 2x. With 8x data acquisition speed-up in the partition-encoding direction, 3D RE-EPI produced acceptable image quality without introduction of noticeable additional artifacts. Due to increased temporal signal-to-noise ratio (tSNR) and better characterization of physiological fluctuations, the new strategy allowed detection of more resting state networks compared to standardmulti-slice two dimensional (2D) EPI and segmented 3D EPI. The approach above suffered from geometry factor (g-factor related) signal-to-noise ratio (SNR) losses, while using very high parallel imaging acceleration factor. To achieve substantial increase in the temporal resolution whilemaintaining low g-factors when high parallel imaging acceleration factors are used, the combination of segmented 3D EPI using 2D controlled aliasing with generalized autocalibrating partially parallel acquisitions (GRAPPA) was implemented in the next approach termed 3D-EPI-CAIPI. FunctionalMRI data with whole-brain coverage, a voxel size of 2 mm isotropic and a temporal resolution of 371 ms was acquired with acceptable image quality. 10-fold parallel imaging accelerated 3D-EPI-CAIPI data was shown to lower g-factor losses by as much as 10% with respect to segmented 3D EPI at 7 Tesla. Additional resting state networks were detected using 3D-EPI-CAIPI compared to a comparable standard 2D EPI acquisition. This was attributed to the improved statistics due to an increased number of volumes acquired in a given duration and because of the improved characterization of physiological signal fluctuations. Functional MRI with 400 ms temporal resolution allowed the detection of time-to-peak variations in temporal, occipital and frontal cortices haemodynamic responses due to multisensory facilitation of the order of ~200 ms. To conclude, this thesis introduces several novel techniques to increase temporal resolution of fMRI. Besides building theoretical foundations for these techniques, their applications for studying human brain functional connectivity, event-related brain activation and the ability to characterize physiological signal fluctuations at ultra-high field strength (7 Tesla) are evaluated.Lausanne, EPFL, 2014.
DOI : 10.5075/epfl-thesis-6395.
Non-invasive diagnostic biomarkers for estimating the onset time of permanent cerebral ischemia
The treatments for ischemic stroke can only be administered in a narrow time-window. However, the ischemia onset time is unknown in ~30% of stroke patients (wake-up strokes). The objective of this study was to determine whether MR spectra of ischemic brains might allow the precise estimation of cerebral ischemia onset time. We modeled ischemic stroke in male ICR-CD1 mice using a permanent middle cerebral artery filament occlusion model with laser Doppler control of the regional cerebral blood flow. Mice were then subjected to repeated MRS measurements of ipsilateral striatum at 14.1[thinsp]T. A striking initial increase in [gamma]-aminobutyric acid (GABA) and no increase in glutamine were observed. A steady decline was observed for taurine (Tau), N-acetyl-aspartate (NAA) and similarly for the sum of NAA Tau glutamate that mimicked an exponential function. The estimation of the time of onset of permanent ischemia within 6[thinsp]hours in a blinded experiment with mice showed an accuracy of 33[plusmn]10[thinsp]minutes. A plot of GABA, Tau, and neuronal marker concentrations against the ratio of acetate/NAA allowed precise separation of mice whose ischemia onset lay within arbitrarily chosen time-windows. We conclude that 1H-MRS has the potential to detect the clinically relevant time of onset of ischemic stroke.
Journal of Cerebral Blood Flow & Metabolism
DOI : 10.1038/jcbfm.2014.155
Optimized MEGA-SPECIAL for in vivo glutamine detection in the rat brain at 14.1 T
Glutamine has multiple roles in brain metabolism and its concentration can be altered in various pathological conditions. An accurate knowledge of its concentration is therefore highly desirable to monitor and study several brain disorders in vivo. However, in recent years, several MRS studies have reported conflicting glutamine concentrations in the human brain. A recent hypothesis for explaining these discrepancies is that a short T2 component of the glutamine signal may impact on its quantification at long echo times. The present study therefore aimed to investigate the impact of acquisition parameters on the quantified glutamine concentration using two different acquisition techniques, SPECIAL at ultra-short echo time and MEGA-SPECIAL at moderate echo time. For this purpose, MEGA-SPECIAL was optimized for the first time for glutamine detection. Based on the very good agreement of the glutamine concentration obtained between the two measurements, it was concluded that no impact of a short T2 component of the glutamine signal was detected.
NMR in Biomedicine
DOI : 10.1002/nbm.3168
Longitudinal neurochemical modifications in the aging mouse brain measured in vivo by 1H magnetic resonance spectroscopy
Alterations to brain homeostasis during development are reflected in the neurochemical profile determined noninvasively by (1)H magnetic resonance spectroscopy. We determined longitudinal biochemical modifications in the cortex, hippocampus, and striatum of C57BL/6 mice aged between 3 and 24 months . The regional neurochemical profile evolution indicated that aging induces general modifications of neurotransmission processes (reduced GABA and glutamate), primary energy metabolism (altered glucose, alanine, and lactate) and turnover of lipid membranes (modification of choline-containing compounds and phosphorylethanolamine), which are all probably involved in the frequently observed age-related cognitive decline. Interestingly, the neurochemical profile was different in male and female mice, particularly in the levels of taurine that may be under the control of estrogen receptors. These neurochemical profiles constitute the basal concentrations in cortex, hippocampus, and striatum of healthy aging male and female mice.
Neurobiology of aging
DOI : 10.1016/j.neurobiolaging.2014.01.135
Image-Derived Input Function from the Vena Cava for 18F-FDG PET Studies in Rats and Mice
Measurement of arterial input function is a restrictive aspect for quantitative 18F-FDG PET studies in rodents because of their small total blood volume and the related difficulties in withdrawing blood. METHODS: In the present study, we took advantage of the high spatial resolution of a recent dedicated small-animal scanner to extract the input function from the 18F-FDG PET images in Sprague-Dawley rats (n = 4) and C57BL/6 mice (n = 5), using the vena cava. In the rat experiments, the validation of the image-derived input function (IDIF) method was made using an external microvolumetric blood counter as reference for the determination of the arterial input function, the measurement of which was confirmed by additional manually obtained blood samples. Correction for tracer bolus dispersion in blood between the vena cava and the arterial tree was applied. In addition, simulation studies were undertaken to probe the impact of the different IDIF extraction approaches on the determined cerebral metabolic rate of glucose (CMRGlc). In the mice measurements, the IDIF was used to compute the CMRGlc, which was compared with previously reported values, using the Patlak approach. RESULTS: The presented IDIF from the vena cava showed a robust determination of CMRGlc using either the compartmental modeling or the Patlak approach, even without bolus dispersion correction or blood sampling, with an underestimation of CMRGlc of 7% /- 16% as compared with the reference data. Using this approach in the mice experiments, we measured a cerebral metabolic rate in the cortex of 0.22 /- 0.10 mumol/g/min (mean /- SD), in good agreement with previous 18F-FDG studies in the mouse brain. In the rat experiments, dispersion correction of the IDIF and additional scaling of the IDIF using a single manual blood sample enabled an optimized determination of CMRGlc, with an underestimation of 6% /- 7%. CONCLUSION: The vena cava time-activity curve is therefore a minimally invasive alternative for the measurement of the 18F-FDG input function in rats and mice, without the complications associated with repetitive blood sampling.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
DOI : 10.2967/jnumed.113.127381
Glutathione Deficit Affects White Matter Integrity in Prefrontal Cortex and Impairs Brain Connectivity in Schizophrenia2014. 69th Annual Scientific Convention and Meeting of the Society-of-Biological-Psychiatry . p. 185S-185S.
Impaired White Matter Integrity in Fornix and Anterior Commissure in a Schizophrenia Mouse Model of Redox Dysregulation2014. 69th Annual Scientific Convention and Meeting of the Society-of-Biological-Psychiatry . p. 175S-175S.
Genetic Association with Prefrontal Glutathione Deficit: A 3T 1H MRS Study in Early Psychosis2014. 69th Annual Scientific Convention and Meeting of the Society-of-Biological-Psychiatry . p. 108S-109S.
Studying glioblastoma progression in a rat model of human glioma initiating cells using 1H MRS and DTI2014. International Society for Magnetic Resonance in Medicine , Milano, Italy , 2014.
Purely endogenous hyperpolarized [1-13C]Pyruvate solutions for metabolic study in glioblastoma rat models2014. International Society for Magnetic Resonance in Medicine , Milano, Italy , 2014.
Metabolic flux analysis of acetylcarnitine turnover and mitochondrial oxidation of [2-13C]acetate in rat skeletal muscle in vivo measured by 13C MRS2014. International Society for Magnetic Resonance in Medicine , Milan, Italy , May 2014. p. 539.
Hyperpolarized 13C lactate as a substrate for in vivo metabolic studies in skeletal muscle2014. International Society for Magnetic Resonance in Medicine , Milan, Italy , May 2014. p. 4025.
Multi-modal assessment of long-term erythropoietin treatment after neonatal hypoxic-ischemic injury in rat brain
Erythropoietin (EPO) has been recognized as a neuroprotective agent. In animal models of neonatal brain injury, exogenous EPO has been shown to reduce lesion size, improve structure and function. Experimental studies have focused on short course treatment after injury. Timing, dose and length of treatment in preterm brain damage remain to be defined. We have evaluated the effects of high dose and long-term EPO treatment in hypoxic-ischemic (HI) injury in 3 days old (P3) rat pups using histopathology, magnetic resonance imaging (MRI) and spectroscopy (MRS) as well as functional assessment with somatosensory-evoked potentials (SEP). After HI, rat pups were assessed by MRI for initial damage and were randomized to receive EPO or vehicle. At the end of treatment period (P25) the size of resulting cortical damage and white matter (WM) microstructure integrity were assessed by MRI and cortical metabolism by MRS. Whisker elicited SEP were recorded to evaluate somatosensory function. Brains were collected for neuropathological assessment. The EPO treated animals did not show significant decrease of the HI induced cortical loss at P25. WM microstructure measured by diffusion tensor imaging was improved and SEP response in the injured cortex was recovered in the EPO treated animals compared to vehicle treated animals. In addition, the metabolic profile was less altered in the EPO group. Long-term treatment with high dose EPO after HI injury in the very immature rat brain induced recovery of WM microstructure and connectivity as well as somatosensory cortical function despite no effects on volume of cortical damage. This indicates that long-term high-dose EPO induces recovery of structural and functional connectivity despite persisting gross anatomical cortical alteration resulting from HI.
DOI : 10.1371/journal.pone.0095643
Experimental peripheral arterial disease: new insights into muscle glucose uptake, macrophage, and T-cell polarization during early and late stages
Peripheral arterial disease (PAD) is a common disease with increasing prevalence, presenting with impaired walking ability affecting patient's quality of life. PAD epidemiology is known, however, mechanisms underlying functional muscle impairment remain unclear. Using a mouse PAD model, aim of this study was to assess muscle adaptive responses during early (1 week) and late (5 weeks) disease stages. Unilateral hindlimb ischemia was induced in ApoE−/− mice by iliac artery ligation. Ischemic limb perfusion and oxygenation (Laser Doppler imaging, transcutaneous oxygen pressure assessments) significantly decreased during early and late stage compared to pre-ischemia, however, values were significantly higher during late versus early phase. Number of arterioles and arteriogenesis-linked gene expression increased at later stage. Walking ability, evaluated by forced and voluntary walking tests, remained significantly decreased both at early and late phase without any significant improvement. Muscle glucose uptake ([18F]fluorodeoxyglucose positron emission tomography) significantly increased during early ischemia decreasing at later stage. Gene expression analysis showed significant shift in muscle M1/M2 macrophages and Th1/Th2 T cells balance toward pro-inflammatory phenotype during early ischemia; later, inflammatory state returned to neutrality. Muscular M1/M2 shift inhibition by a statin prevented impaired walking ability in early ischemia. High-energy phosphate metabolism remained unchanged (31-Phosphorus magnetic resonance spectroscopy). Results show that rapid transient muscular inflammation contributes to impaired walking capacity while increased glucose uptake may be a compensatory mechanisms preserving immediate limb viability during early ischemia in a mouse PAD model. With time, increased ischemic limb perfusion and oxygenation assure muscle viability although not sufficiently to improve walking impairment. Subsequent decreased muscle glucose uptake may partly contribute to chronic walking impairment. Early inflammation inhibition and/or late muscle glucose impairment prevention are promising strategies for PAD management.
DOI : 10.1002/phy2.234
Clinical Proton MR Spectroscopy in Central Nervous System Disorders
A large body of published work shows that proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of (1)H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of (1)H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which (1)H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units.
DOI : 10.1148/radiol.13130531
Are glutamate and lactate increases ubiquitous to physiological activation? A 1H functional MR spectroscopy study during motor activation in human brain at 7Tesla
Recent studies at high field (7 Tesla) have reported small metabolite changes, in particular lactate and glutamate (below 0.3 μmol/g) during visual stimulation. These studies have been limited to the visual cortex because of its high energy metabolism and good magnetic resonance spectroscopy (MRS) sensitivity using surface coil. The aim of this study was to extend functional MRS (fMRS) to investigate for the first time the metabolite changes during motor activation at 7 T. Small but sustained increases in lactate (0.17 μmol/g ± 0.05 μmol/g, p < 0.001) and glutamate (0.17 μmol/g ± 0.09 μmol/g, p < 0.005) were detected during motor activation followed by a return to the baseline after the end of activation. The present study demonstrates that increases in lactate and glutamate during motor stimulation are small, but similar to those observed during visual stimulation. From the observed glutamate and lactate increase, we inferred that these metabolite changes may be a general manifestation of the increased neuronal activity. In addition, we propose that the measured metabolite concentration increases imply an increase in ΔCMRO2 that is transiently below that of ΔCMRGlc during the first 1 to 2 minutes of the stimulation.
DOI : 10.1016/j.neuroimage.2014.02.016
In vivo brain macromolecule signals in healthy and glioblastoma mouse models: 1H magnetic resonance spectroscopy, post-processing and metabolite quantification at 14.1 T
In 1H magnetic resonance spectroscopy, macromolecule signals underlay metabolite signals, the understanding of which is necessary for reliable metabolite quantification. When macromolecule signals are measured using an inversion-recovery pulse sequence, special care needs to be taken to correctly remove residual metabolite signals to obtain a pure macromolecule spectrum. Furthermore, since a single spectrum is commonly used for quantification in multiple experiments, the impact of potential macromolecule signal variability, due to regional differences or pathologies, on metabolite quantification has to be assessed. In this study, we introduced a novel method to post-process measured macromolecule signals that offers a flexible and robust way of removing residual metabolite signals. This method was applied to investigate regional differences in the mouse brain macromolecule signals that may affect metabolite quantification when not taken into account. However, since no significant differences in metabolite quantification were detected, it was concluded that a single macromolecule spectrum can be generally used for the quantification of healthy mouse brain spectra. Alternatively, the study of a mouse model of human glioma showed several alterations of the macromolecule spectrum, including, but not limited to, increased mobile lipids signals, which had to be taken into account to avoid significant metabolite quantification errors.
Journal of Neurochemistry
DOI : 10.1111/jnc.12673
Definition and quantification of acute inflammatory white matter injury in the immature brain by MRI/MRS at high magnetic field
Background: Intrauterine growth restriction (IUGR) is a major risk factor for both perinatal and long-term morbidity. Bovine lactoferrin (bLf) is a major milk glycoprotein considered as a pleiotropic functional nutrient. The impact of maternal supplementation with bLf on IUGR-induced sequelae, including inadequate growth and altered cerebral development, remains unknown. Methods: IUGR was induced through maternal dexamethasone infusion (100 μg/kg during last gestational week) in rats. Maternal supplementation with bLf (0.85% in food pellet) was provided during both gestation and lactation. Pup growth was monitored, and Pup brain metabolism and gene expression were studied using in vivo 1H NMR spectroscopy, quantitative PCR, and microarray in the hippocampus at postnatal day (PND)7. Results: Maternal bLf supplementation did not change gestational weight but increased the birth body weight of control pups (4%) with no effect on the IUGR pups. Maternal bLf supplementation allowed IUGR pups to recover a normalized weight at PND21 (weaning) improving catch-up growth. Significantly altered levels of brain metabolites (γ-aminobutyric acid, glutamate, N-acetylaspartate, and N-acetylaspartylglutamate) and transcripts (brain-derived neurotrophic factor (BDNF), divalent metal transporter 1 (DMT-1), and glutamate receptors) in IUGR pups were normalized with maternal bLf supplementation. Conclusion: Our data suggest that maternal bLf supplementation is a beneficial nutritional intervention able to revert some of the IUGR-induced sequelae, including brain hippocampal changes.
DOI : 10.1038/pr.2013.242
Protective effects of maternal nutritional supplementation with lactoferrin on growth and brain metabolism
Background:Intrauterine growth restriction (IUGR) is a major risk factor for both perinatal and long-term morbidity. Bovine lactoferrin (bLf) is a major milk glycoprotein considered as a pleiotropic functional nutrient. The impact of maternal supplementation with bLf on IUGR-induced sequelae, including inadequate growth and altered cerebral development, remains unknown.Methods:IUGR was induced through maternal dexamethasone infusion (100 mug/kg during last gestational week) in rats. Maternal supplementation with bLf (0.85% in food pellet) was provided during both gestation and lactation. Pup growth was monitored, and Pup brain metabolism and gene expression were studied using in vivo (1)H NMR spectroscopy, quantitative PCR, and microarray in the hippocampus at postnatal day (PND)7.Results:Maternal bLf supplementation did not change gestational weight but increased the birth body weight of control pups (4%) with no effect on the IUGR pups. Maternal bLf supplementation allowed IUGR pups to recover a normalized weight at PND21 (weaning) improving catch-up growth. Significantly altered levels of brain metabolites (gamma-aminobutyric acid, glutamate, N-acetylaspartate, and N-acetylaspartylglutamate) and transcripts (brain-derived neurotrophic factor (BDNF), divalent metal transporter 1 (DMT-1), and glutamate receptors) in IUGR pups were normalized with maternal bLf supplementation.Conclusion:Our data suggest that maternal bLf supplementation is a beneficial nutritional intervention able to revert some of the IUGR-induced sequelae, including brain hippocampal changes.
DOI : 10.1038/pr.2013.199
Hyperpolarized 13C lactate as a substrate for in vivo metabolic studies in skeletal muscle
Resting skeletal muscle has a preference for the oxidation of lipids compared to carbohydrates and a shift towards carbohydrate oxidation is observed with increasing exercise. Lactate is not only an end product in skeletal muscle but also an important metabolic intermediate for mitochondrial oxidation. Recent advances in hyperpolarized MRS allow the measurement of substrate metabolism in vivo in real time. The aim of this study was to investigate the use of hyperpolarized 13C lactate as a substrate for metabolic studies in skeletal muscle in vivo. Carbohydrate metabolism in healthy rat skeletal muscle at rest was studied in different nutritional states using hyperpolarized [1-13C]lactate, a substrate that can be injected at physiological concentrations and leaves other oxidative processes undisturbed. 13C label incorporation from lactate into bicarbonate in fed animals was observed within seconds but was absent after an overnight fast, representing inhibition of the metabolic flux through pyruvate dehydrogenase (PDH). A significant decrease in 13C labeling of alanine was observed comparing the fed and fasted group, and was attributed to a change in cellular alanine concentration and not a decrease in enzymatic flux through alanine transaminase. We conclude that hyperpolarized [1-13C]lactate can be used to study carbohydrate oxidation in resting skeletal muscle at physiological levels. The herein proposed method allows probing simultaneously both PDH activity and variations in alanine tissue concentration, which are associated with metabolic dysfunctions. A simple alteration of the nutritional state demonstrated that the observed pyruvate, alanine, and bicarbonate signals are indeed sensitive markers to probe metabolic changes in vivo.
DOI : 10.1007/s11306-014-0630-5
MRS glucose mapping and PET joining forces: Re-evaluation of the lumped constant in the rat brain under isoflurane anaesthesia
Although numerous positron emission tomography (PET) studies with ((8) F-fluoro-deoxyglucose) FDG have reported quantitative results on cerebral glucose kinetics and consumption, there is a large variation between the absolute values found in the literature. One of the underlying causes is the inconsistent use of the lumped constants (LCs), the derivation of which is often based on multiple assumptions that render absolute numbers imprecise and errors hard to quantify. We combined a kinetic FDG-PET study with magnetic resonance spectroscopic imaging (MRSI) of glucose dynamics in Sprague-Dawley rats to obtain a more comprehensive view of brain glucose kinetics and determine a reliable value for the LC under isoflurane anaesthesia. Maps of Tmax /CMRglc derived from MRSI data and Tmax determined from PET kinetic modeling allowed to obtain an LC-independent CMRglc . The LC was estimated to range from 0.33±0.07 in retrosplenial cortex to 0.44±0.05 in hippocampus, yielding CMRglc between 62±14 and 54±11 μmol/min/100g, respectively. These newly determined LCs for four distinct areas in the rat brain under isoflurane anaesthesia provide means of comparing the growing amount of FDG-PET data available from translational studies. This article is protected by copyright. All rights reserved.
Journal of neurochemistry
DOI : 10.1111/jnc.12667
Localized Single-Voxel Magnetic Resonance Spectroscopy, Water Suppression, and Novel Approaches for Ultrashort Echo-time Measurements
Single-voxel proton MRS can be obtained with inversion-based, echo-based, and hybrid methods. Yet, standard localization methods do not guarantee quality. Therefore, knowing basic principles, such as influence factors on both volume definition and spectral quality, including radiofrequency pulses, gradients, chemical shift errors, water-suppression techniques, and outer volume suppression, is very important. In this chapter, we describe factors affecting performance of short echo-time single-voxel proton spectroscopy and currently available localization methods for 1H MRS.Magnetic Resonance Spectroscopy: Tools for Neuroscience Research and Emerging Clinical Applications; Academic Press,
DOI : 10.1016/B978-0-12-401688-0.00002-1.
Phase-based manganese enhanced MRI, a new methodology to enhance brain cytoarchitectural contrast and study manganese uptake
Purpose As the magnetic susceptibility induced frequency shift increases linearly with magnetic field strength, the present work evaluates manganese as a phase imaging contrast agent and investigates the dose dependence of brain enhancement in comparison to T1-weighted imaging after intravenous administration of MnCl2. Methods Experiments were carried out on 12 Sprague-Dawley rats. MnCl2 was infused intravenously with the following doses: 25, 75, 125 mg/kg (n=4). Phase, T1-weighted images and T1 maps were acquired before and 24h post MnCl2 administration at 14.1 Tesla. Results Manganese enhancement was manifested in phase imaging by an increase in frequency shift differences between regions rich in calcium gated channels and other tissues, together with local increase in signal to noise ratio (from the T1 reduction). Such contrast improvement allowed a better visualization of brain cytoarchitecture. The measured T1 decrease observed across different manganese doses and in different brain regions were consistent with the increase in the contrast to noise ratio (CNR) measured by both T1-weighted and phase imaging, with the strongest variations being observed in the dentate gyrus and olfactory bulb. Conclusion Overall from its high sensitivity to manganese combined with excellent CNR, phase imaging is a promising alternative imaging protocol to assess manganese enhanced MRI at ultra high field.
Magnetic Resonance in Medicine
DOI : 10.1002/mrm.25037
Is the macromolecule signal tissue-specific in healthy human brain? A 1H MRS study at 7 tesla in the occipital lobe
Purpose The macromolecule signal plays a key role in the precision and the accuracy of the metabolite quantification in short-TE 1H MR spectroscopy. Macromolecules have been reported at 1.5 Tesla (T) to depend on the cerebral studied region and to be age specific. As metabolite concentrations vary locally, information about the profile of the macromolecule signal in different tissues may be of crucial importance. Methods The aim of this study was to investigate, at 7T for healthy subjects, the neurochemical profile differences provided by macromolecule signal measured in two different tissues in the occipital lobe, predominantly composed of white matter tissue or of grey matter tissue. Results White matter-rich macromolecule signal was relatively lower than the gray matter-rich macromolecule signal from 1.5 to 1.8 ppm and from 2.3 to 2.5 ppm with mean difference over these regions of 7% and 12% (relative to the reference peak at 0.9 ppm), respectively. The neurochemical profiles, when using either of the two macromolecule signals, were similar for 11 reliably quantified metabolites (CRLB < 20%) with relatively small concentration differences (< 0.3 μmol/g), except Glu (± 0.8 μmol/g). Conclusion Given the small quantification differences, we conclude that a general macromolecule baseline provides a sufficiently accurate neurochemical profile in occipital lobe at 7T in healthy human brain.
Magnetic Resonance in Medicine
DOI : 10.1002/mrm.24995
Improved temporal resolution for functional studies with reduced number of segments with three-dimensional echo planar imaging
PURPOSE: To introduce a new k-space traversal strategy for segmented three-dimensional echo planar imaging (3D EPI) that encodes two partitions per radiofrequency excitation, effectively reducing the number excitations used to acquire a 3D EPI dataset by half. METHODS: The strategy was evaluated in the context of functional MRI applications for: image quality compared with segmented 3D EPI, temporal signal-to-noise ratio (tSNR) (the ability to detect resting state networks compared with multislice two-dimensional (2D) EPI and segmented 3D EPI, and temporal resolution (the ability to separate cardiac- and respiration-related fluctuations from the desired blood oxygen level-dependent signal of interest). RESULTS: Whole brain images with a nominal voxel size of 2 mm isotropic could be acquired with a temporal resolution under half a second using traditional parallel imaging acceleration up to 4x in the partition-encode direction and using novel data acquisition speed-up of 2x with a 32-channel coil. With 8x data acquisition speed-up in the partition-encode direction, 3D reduced excitations (RE)-EPI produced acceptable image quality without introduction of noticeable additional artifacts. Due to increased tSNR and better characterization of physiological fluctuations, the new strategy allowed detection of more resting state networks compared with multislice 2D-EPI and segmented 3D EPI. CONCLUSION: 3D RE-EPI resulted in significant increases in temporal resolution for whole brain acquisitions and in improved physiological noise characterization compared with 2D-EPI and segmented 3D EPI.
Magnetic Resonance in Medicine
DOI : 10.1002/mrm.24975
In vivo quantification of neuro-glial metabolism and glial glutamate concentration using 1H-[13C] MRS at 14.1T
Astrocytes have recently become a major center of interest in neurochemistry with the discoveries on their major role in brain energy metabolism. An interesting way to probe this glial contribution is given by in vivo 13C NMR spectroscopy coupled with the infusion labeled glial-specific substrate, such as acetate. In this study, we infused alpha-chloralose anesthetized rats with [2-13C]acetate and followed the dynamics of the fractional enrichment in the positions C4 and C3 of glutamate and glutamine with high sensitivity, using 1H-[13C] MRS at 14.1T. Applying a two-compartment mathematical model to the measured time courses yielded a glial TCA cycle rate (Vg) of 0.27 ± 0.02 μmol/g/min and a glutamatergic neurotransmission rate (VNT) of 0.15 ± 0.01 μmol/g/min. Glial oxidative ATP metabolism thus accounts for 38% of total oxidative metabolism measured by NMR. Pyruvate carboxylase (VPC) was 0.09 ± 0.01 μmol/g/min, corresponding to 37% of the glial glutamine synthesis rate. The glial and neuronal transmitochondrial fluxes (Vxg and Vxn) were of the same order of magnitude as the respective TCA cycle fluxes. Additionally, we estimated a glial glutamate pool size of 0.6 ± 0.1 μmol/g. The effect of spectral data quality on the fluxes estimates was analyzed by Monte Carlo simulations.
Journal of Neurochemistry
DOI : 10.1111/jnc.12479
An improved trap design for decoupling multinuclear RF coils
Purpose Multinuclear magnetic resonance spectroscopy and imaging require a radiofrequency probe capable of transmitting and receiving at the proton and non-proton frequencies. To minimize coupling between probe elements tuned to different frequencies, LC (inductor-capacitor) traps blocking current at the 1H frequency can be inserted in non-proton elements. This work compares LC traps with LCC traps, a modified design incorporating an additional capacitor, enabling control of the trap reactance at the low frequency while maintaining 1H blocking. Methods Losses introduced by both types of trap were analysed using circuit models. Radiofrequency coils incorporating a series of LC and LCC traps were then built and evaluated at the bench. LCC trap performance was then confirmed using 1H and 13C measurements in a 7T human scanner. Results LC and LCC traps both effectively block interaction between non-proton and proton coils at the proton frequency. LCC traps were found to introduce a sensitivity reduction of 5±2%, which was less than half of that caused by LC traps. Conclusion Sensitivity of non-proton coils is critical. The improved trap design, incorporating one extra capacitor, significantly reduces losses introduced by the trap in the non-proton coil.
Magnetic Resonance in Medicine
DOI : 10.1002/mrm.24931
Improving T2 -weighted imaging at high field through the use of kT -points
PURPOSE: At high magnetic field strengths (B0 >/= 3 T), the shorter radiofrequency wavelength produces an inhomogeneous distribution of the transmit magnetic field. This can lead to variable contrast across the brain which is particularly pronounced in T2 -weighted imaging that requires multiple radiofrequency pulses. To obtain T2 -weighted images with uniform contrast throughout the whole brain at 7 T, short (2-3 ms) 3D tailored radiofrequency pulses (kT -points) were integrated into a 3D variable flip angle turbo spin echo sequence. METHODS: The excitation and refocusing "hard" pulses of a variable flip angle turbo spin echo sequence were replaced with kT -point pulses. Spatially resolved extended phase graph simulations and in vivo acquisitions at 7 T, utilizing both single channel and parallel-transmit systems, were used to test different kT -point configurations. RESULTS: Simulations indicated that an extended optimized k-space trajectory ensured a more homogeneous signal throughout images. In vivo experiments showed that high quality T2 -weighted brain images with uniform signal and contrast were obtained at 7 T by using the proposed methodology. CONCLUSION: This work demonstrates that T2 -weighted images devoid of artifacts resulting from B1 inhomogeneity can be obtained at high field through the optimization of extended kT -point pulses.
Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine
DOI : 10.1002/mrm.24805
Human finger somatotopy in areas 3b, 1, and 2: A 7T fMRI study using a natural stimulus
To study the properties of human primary somatosensory (S1) cortex as well as its role in cognitive and social processes, it is necessary to noninvasively localize the cortical representations of the body. Being arguably the most relevant body parts for tactile exploration, cortical representations of fingers are of particular interest. The aim of the present study was to investigate the cortical representation of individual fingers (D1-D5), using human touch as a stimulus. Utilizing the high BOLD sensitivity and spatial resolution at 7T, we found that each finger is represented within three subregions of S1 in the postcentral gyrus. Within each of these three areas, the fingers are sequentially organized (from D1 to D5) in a somatotopic manner. Therefore, these finger representations likely reflect distinct activations of BAs 3b, 1, and 2, similar to those described in electrophysiological work in non-human primates. Quantitative analysis of the local BOLD responses revealed that within BA3b, each finger representation is specific to its own stimulation without any cross-finger responsiveness. This finger response selectivity was less prominent in BA 1 and in BA 2. A test-retest procedure highlighted the reproducibility of the results and the robustness of the method for BA 3b. Finally, the representation of the thumb was enlarged compared to the other fingers within BAs 1 and 2. These findings extend previous human electrophysiological and neuroimaging data but also reveal differences in the functional organization of S1 in human and nonhuman primates. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.
Human brain mapping
DOI : 10.1002/hbm.22172
In vivo brain energy metabolism in a rat model of chronic Hepatic Encephalopathy using 31P MRS2013. 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases', u'64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases' . p. 393A-393A.
Tapping into the brain: An ultra-high resolution investigation of the sensory-motor system using 7-Tesla fMRI2013. 21st Annual Meeting of the Israel-Society-for-Neuroscience / 1st Binational Australian-Israeli Meeting on Neuroscience . p. S104-S104.
Development and implementation of ¹H magnetic resonance techniques for an improved in vivo assessment of models of cerebral metabolic disorders
Nuclear magnetic resonance (NMR) is a physical phenomenon that is widely used in the biomedical field due to its non-invasive and non-destructive properties, which make it an optimal tool for the in vivo investigation of living organs such as the brain. This thesis focused on the development of 1H magnetic resonance (MR) techniques at ultra-high magnetic field strength to improve the measurement and quantification of the 1H MR signal in the rodent brain, and to accurately assess the alterations of the metabolite and water concentrations in several cerebral metabolic disorders. In rodents, 1H MR spectroscopy (MRS) allows the assessment of the concentration of up to 20 metabolites that take part in many cerebral metabolic processes such as neurotransmission, cell energy metabolism, cell growth and osmosis. 1H MRS thus provides a unique tool to non-invasively investigate the cerebral metabolism in healthy and pathological conditions in vivo. However, it is essential for reliable quantification that systematic errors and overlap of the measured metabolite signals are minimized. To that aim, the impact of a potential additional short T2 relaxation time component, which might affect the glutamine quantification at long echo times, was assessed in this thesis. The J-difference editing technique MEGA-SPECIAL was optimized to obtain the unequivocal detection of the glutamine signal at moderate echo time. As a control, the glutamine concentration obtained with this method was then compared to short echo time 1H MR spectroscopy measurements. Since the two measurements of the glutamine concentration at short and moderate echo time did not result in significant differences, this study concluded that there is a low probability of an effect of a short T2 relaxation time component on the glutamine concentration measurement. Since a reliable quantification of 1H spectra partly relies on the accurate assessment of the overlapping macromolecule contribution to the metabolites, an optimized method for the post-processing of the measured macromolecule signal was developed to ensure an accurate assessment of its contribution. This method was applied to investigate potential regional differences in the mouse brain macromolecule signals that may affect metabolite quantification when not taken into account, as well as for the assessment of macromolecule alterations in a human-glioma mouse model. No regional macro- molecule variation was found to significantly affect the metabolite quantification in the healthy mouse brain, which supports the common use of a general macromolecule spec- trum for healthy rodent brain 1H spectra quantification. However, several alterations of the macromolecule spectrum, some of which were reported for the first time, were observed in glioma tissues, and their accurate assessment was shown to be necessary for reliable metabolite quantification. Localized 1H MR spectroscopy techniques that are designed to acquire the1H MR signal from a 3D volume can also be combined with MR imaging (MRI) to acquire information on the spatial distribution of the individual metabolites, which is often of interest when heterogeneous tissues are investigated (such as in pathological conditions). This MR spectroscopic imaging (MRSI) technique is however limited in its conventional implementation by the long measurement time that is necessary to acquire the spatial information. A fast MRSI technique, spectroscopic RARE (spRARE), was therefore implemented at high magnetic field strength in this thesis in order to benefit from the advantage of high magnetic fields in addition to the rapid spatial encoding scheme offered by spRARE. Several optimizations of the metabolite signal detection were implemented in spRARE, before the efficiency of the technique was validated at 9.4 T through a comparison of the acquired in vitro metabolite signals with numerical simulations using the density matrix formalism. The in vivo quantification of the water content is also of interest as it offers perspec- tives for investigating cerebral disease progression that is associated with brain water content alterations. In addition, when the water signal is used as an internal reference for metabolite concentration quantification in MRS, such knowledge can also contribute to a more reliable quantification. A method that is based on the multi-spin-echo MRI technique was therefore developed for the absolute quantification of the water content in the rodent brain, with the aim of assessing alterations of its content in pathological conditions. It was then applied on a bile-duct-ligation rat model of chronic hepatic encephalopathy (HE) to assess the brain water content changes associated with the disease as well as its metabolic alterations. The absence of significant brain water content changes detected in the investigated HE rat model, which was supported by post-mortem brain water content measurements using gravimetry and the dry/wet weight-ratio technique, potentially opens the way for investigating cerebral metabolic processes in chronic HE in absence of edema formation. Localized 1H MRS and conventional MRSI were also applied for the investigation of rodent models of brain disorders in order to assess the metabolic profile associated with those disorders. These studies for the first time allowed the assessment of GABA as a potential early Parkinson’s disease marker, while they also provided new insights into the role of the PPAR-β brain receptor in the early neuroprotective effects following ischemia.Lausanne, EPFL, 2013.
DOI : 10.5075/epfl-thesis-5987.
Methods for Molecular Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy using Hyperpolarized Nuclei
Since the introduction 10 years ago of the dissolution method, Dynamic Nuclear Polarization (DNP) became a widely applied and powerful technique to enhance nuclear magnetic resonance (NMR) signals of low naturally abundant, insensitive nuclear spins for analytical chemistry and biomedical research. The aim of DNP is to obtain a very high degree of polarization on the nuclei of interest in cryogenic conditions (i.e. 1 K ), a hundred or more times higher than the thermal polarization. Then, trough a fast dissolution process the molecules hosting the nuclear spins are mixed in a room temperature solution and, since their polarization is conserved if their relaxation times are long enough, they can be used for in vitro or in vivo experiments with a SNR enhanced by 104 times or more. Although the DNP technique was established about 60 years ago, the hardware and cryogenic equipment needed to perform DNP and the subsequent dissolution, still are a technological challenge. In this thesis we will cover different DNP aspects, ranging from hardware installation, software development, solid state measurement, in vitro and in vivo experiments and a possible application of DNP to MRI studies of granular materials. A new DNP cryostat was developed and tested to determine its cryogenic performances and then optimized for fast cooldown, helium holdtime and overall minimal operational consumption. We will show the characteristics of the cryostat and the performances on standard operations like cooling and DNP at 1 K . Another important aspect the development tackled was automation. The management of the system was condensed in a single electronic box capabile to handle the interface with all the cryostat instruments. This box is driven by a single common USB port trough a custom made software interface we developed. Although a few manual operations are still needed, we achieved a high degree of automation. The solid state polarization enhancement ε is defined as the ratio between the DNP enhanced and the thermal polarization signals. It can be determined by measuring the DNP enhanced signal after the system stabilizes in the polarized state (i.e. after about 5 buildup time) and thermal polarization signal after the spins have fully relaxed to equilibrium (i.e. after about 5T1). As a first application of the new system, we present a method that exploits the behavior of steady states magnetization produced with trains of evenly spaced pulses, at constant flip angle. This method allows to precisely determine the thermally polarized signal of a sample with known T1 and a given flip angle in a small fraction (as low as half of a T1 or less depending on the requested accuracy) of the time needed in the usual "wait 5 T1 and pulse" scheme. The main drawback of the dissolution DNP is that the large polarization achieved will ineluctably relax towards its thermal equilibrium value in a few times T1, that for typical 13C labeled molecules is shorter than a minute. On the other hand some nuclei as 6Li and quaternary 15N show a very long T1 on the order of few minutes in biological conditions, allowing measurements as long as several minutes. 6Li is very sensitive to contrast agents such as Gd-doped contrast agents, O2 and de-oxygenated hemoglobin. We studied the effect of the oxygenation of human and rat blood on the 6Li T1, showing clear changes between oxygenated and de-oxygenated samples. Thus we showed that 6Li could be used to map blood oxygenation levels in vitro, and suggest possible in vivo applications, even in brain due to its capability to easily pass the blood brain barrier. 15N labeled choline has a very long 15N T1 and can be used to probe rate of transport or metabolism in brain. Although it has a long T1, the spectral dispersion between the precursor, choline, and its metabolites is very small. The spectral dispersion is much larger for 1 H spins and thus being able to partially transfer repeatedly the 15N to 1H before detection would greatly increase the spectral separation between metabolites while still being able to measure the time course of the metabolic process, which is not the case with a full transfer like with INEPT. We demonstrate that a Hartmann–Hahn polarization transfer can be used to partially transfer the hyperpolarization of 15N to surrounding 1H before detection on 1H. This method can then be applied to in vivo DNP experiments. Even with a very high signal it is very difficult to quantify metabolites that are very close in the NMR spectrum, compared to the actual in vivo linewidth. To improve the spectral resolution it is worth performing the experiments in high magnetic fields. We show the first in vivo rat muscle DNP measurement of acetate at 14.1 T , to resolve e.g. the glutamate peak from acetate substrate. Finally we discuss a segmentation algorithm used to precisely reconstruct granular samples composed of up to 104 spheres. We used a standard Gradient Echo imaging sequence on a Siemens 7 T MRI human scanner to obtain high resolution images of a phantom composed of a cylinder filled with Cu2 doped water and plastic spheres. Then the 3D images where segmented trough a thresholded Hugh transform method and the beads centers determined. The datasets were studied to extract structural and geometrical information.Lausanne, EPFL, 2013.
DOI : 10.5075/epfl-thesis-5966.
Metabolic Flux and Compartmentation Analysis in the Brain In vivo
Through significant developments and progresses in the last two decades, in vivo localized nuclear magnetic resonance spectroscopy (MRS) became a method of choice to probe brain metabolic pathways in a non-invasive way. Beside the measurement of the total concentration of more than 20 metabolites, 1H MRS can be used to quantify the dynamics of substrate transport across the blood brain barrier (BBB) by varying the plasma substrate level. On the other hand, 13C MRS with the infusion of 13C enriched substrates enables the characterization of brain oxidative metabolism and neurotransmission by incorporation of 13C in the different carbon positions of amino acid neurotransmitters. The quantitative determination of the biochemical reactions involved in these processes requires the use of appropriate metabolic models, whose level of details is strongly related to the amount of data accessible with in vivo MRS. In the present work, we present the different steps involved in the elaboration of a mathematical model of a given brain metabolic process and its application to the experimental data in order to extract quantitative brain metabolic rates. We review the recent advances in the localized measurement of brain glucose transport and compartmentalized brain energy metabolism, and how these reveal mechanistic details on glial support to glutamatergic and GABAergic neurons.
Frontiers in Endocrinology
DOI : 10.3389/fendo.2013.00156
Direct mapping of 19F in 19FDG-6P in brain tissue at subcellular resolution using soft X-ray fluorescence
Low energy x-ray fluorescence (LEXRF) detection was optimized for imaging cerebral glucose metabolism by mapping the fluorine LEXRF signal of 19 F in 19 FDG, trapped as intracellular 19 F-deoxyglucose-6-phosphate ( 19 FDG-6P) at 1μm spatial resolution from 3μm thick brain slices. 19 FDG metabolism was evaluated in brain structures closely resembling the general cerebral cytoarchitecture following formalin fixation of brain slices and their inclusion in an epon matrix. 2-dimensional distribution maps of 19 FDG-6P were placed in a cytoarchitectural and morphological context by simultaneous LEXRF mapping of N and O, and scanning transmission x-ray (STXM) imaging. A disproportionately high uptake and metabolism of glucose was found in neuropil relative to intracellular domains of the cell body of hypothalamic neurons, showing directly that neurons, like glial cells, also metabolize glucose. As 19 F-deoxyglucose-6P is structurally identical to 18 F-deoxyglucose-6P, LEXRF of subcellular 19 F provides a link to in vivo 18 FDG PET, forming a novel basis for understanding the physiological mechanisms underlying the 18 FDG PET image, and the contribution of neurons and glia to the PET signal.
Journal of Physics: Conference Series
DOI : 10.1088/1742-6596/463/1/012003
Brain Glucose Transport and Phosphorylation Under Acute Insulin-Induced Hypoglycemia in Mice: An 18F-FDG PET Study
We addressed the questions of how cerebral glucose transport and phosphorylation change under acute hypoglycemia and what the underlying mechanisms of adaptation are. Methods: Quantitative 18F-FDG PET combined with the acquisition of real-time arterial input function was performed on mice. Hypoglycemia was induced and maintained by insulin infusion. PET data were analyzed with the 2-tissue-compartment model for 18F-FDG, and the results were evaluated with Michaelis–Menten saturation kinetics. Results: Glucose clearance from plasma to brain (K1,glc) and the phosphorylation rate constant increased with decreasing plasma glucose (Gp), in particular at a Gp of less than 2.5 mmol/L. Estimated cerebral glucose extraction ratios taking into account an increased cerebral blood flow (CBF) at a Gp of less than 2 mmol/L were between 0.14 and 0.79. CBF-normalized K1,glc values were in agreement with saturation kinetics. Phosphorylation rate constants indicated intracellular glucose depletion at a Gp of less than 2–3 mmol/L. When brain regions were compared, glucose transport under hypoglycemia was lowest in the hypothalamus. Conclusion: Alterations in glucose transport and phosphorylation, as well as intracellular glucose depletion, under acute hypoglycemia can be modeled by saturation kinetics taking into account an increase in CBF. Distinct transport kinetics in the hypothalamus may be involved in its glucose-sensing function.
Journal of Nuclear Medicine
DOI : 10.2967/jnumed.113.122812
In vivo brain energy metabolism in a rat model of chronic Hepatic Encephalopathy using 31P MRS2013. The 64th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2013 , Washington, DC , November 1 - 5, 2013. p. 379.
In vivo metabolic studies in skeletal and cardiac muscle using ¹³C magnetic resonance spectroscopy
Cardiac and skeletal muscle function relies on a continuous energy production via fatty acid metabolism and mitochondrial oxidation of pyruvate, with a fine balance between substrate delivery and utilization. Changes in metabolism are increasingly being implicated as playing an intrinsic role in many diseases, such as diabetes, cancer, and heart failure. Investigating and identifying fundamental metabolic processes are paramount to understanding pathologies. Beyond morphology and functional information, magnetic resonance can provide insights at a metabolic level using spectroscopic techniques such as 13C NMR. The low natural abundance and sensitivity of the 13C nucleus makes 13C NMR in biological systems challenging. In addressing this issue, hyperpolarized methods have emerged as a very promising tool, obtaining signal enhancements up to 10,000 fold. Spectra of hyperpolarized 13C labeled substrates and their downstream metabolic products offer insight into metabolic processes occurring in vivo within seconds after the injection. This thesis focused on the development of MR hyperpolarization methods and applications to study energy metabolism in cardiac and skeletal muscle in vivo. This ranged from development of the experimental frame work to mathematical tools to characterize the observed metabolic processes. Methods were developed to visualize 13C labeling kinetics of acetylcarnitine in vivo in resting skeletal muscle following the administration of hyperpolarized [1-13C]acetate. Two different, novel mathematical models were constructed to quantify the kinetic rate constants. Although separated by two enzymatic reactions, the conversion of acetate to acetylcarnitine was uniquely defined by the enzymatic activity of acetylCoA synthetase (ACS). A 13C MRS protocol was developed and implemented for hyperpolarized studies in the heart, which included selecting appropriate cardiac triggers to align the measurements with the cardiac phase. The 13C label propagation into acetylcarnitine and citrate could be measured in real time in the beating rat heart following the infusion of hyperpolarized [1-13C]acetate, using a newly constructed 13C RF coil which improved the detection sensitivity. The substantial spectral resolution at 9.4T and a triggered shimming and MR acquisition protocol allowed for the detection of citrate for the first time in vivo after injection of hyperpolarized [1-13C]acetate. Mathematical models were successfully extended to include mitochondrial oxidation and analytical expressions were derived to interpret the dynamic 13C labeling of citrate. Cardiac dysfunction is often associated with a shift in substrate preference, while diagnostic methods such as PET provide only information on substrate uptake. The potential of hyperpolarized 13C MRS to measure simultaneously lipid and carbohydrate oxidation was demonstrated in vivo, and the sensitivity of the method to a metabolic perturbation was assessed. Hyperpolarized [1-13C]butyrate and [1-13C]pyruvate were used as representatives of carbohydrate and lipid oxidation. Fasting led to significant changes in preference for the injected substrates. The appearance of a cohort of downstream metabolites (bicarbonate, lactate, alanine, glutamate, citrate, acetylcarnitine, β-hydroxybutyrate and acetoacetate) allowed the independent and simultaneous monitoring of myocardial oxidation of both fatty acid and carbohydrates in vivo and is a sensitive indicator of metabolic shift. Lactate is an important metabolic intermediate for mitochondrial oxidation. Carbohydrate metabolism in healthy rat skeletal muscle at rest was studied in different nutritional states using hyperpolarized [1-13C]lactate, which can be injected at physiological concentrations and leaves other oxidative processes undisturbed. A significant decrease in [1-13C]alanine and 13C bicarbonate were observed comparing both groups, attributed to a change in cellular alanine concentration and pyruvate dehydrogenase (PDH) flux. It was shown that lactate can be used to study carbohydrate oxidation in skeletal muscle at physiological levels and that the downstream metabolite signals are sensitive markers to probe metabolic changes. Since the detection of [5-13C]citrate and [5-13C]glutamate in the heart is hindered by the close proximity of the [1-13C]acetate resonance, acetylcarnitine could be an interesting substrate for hyperpolarized MR. Acetylcarnitine crosses the mitochondrial membrane easily, while skipping a few metabolic steps needed for acetate to cross the membrane. Moreover, it does not interfere with the detection of [5-13C]glutamate and [5-13C]citrate. [1-13C]Acetylcarnitine was successfully hyperpolarized and despite its short T1 it was possible to detect the formation of [5-13C]glutamate in the heart in vivo. Due to the absence of the [5-13C]citrate resonance, we hypothesized the existence of an intricate relationship between reaction, transport and relaxation rates in the choice of hyperpolarized substrates. Acetylcarnitine has relatively small poolsizes and has only been observed using hyperpolarized 13C MRS techniques. Therefore, it has not been possible to obtain reliable quantification of the metabolic turnover of acetylcarnitine, which is an essential intermediate in the metabolism of acetate. Methods were implemented to measure the oxidation of [2-13C]acetate locally with increased sensitivity at high field (14.1T), using a 1H-13C polarization transfer sequence. This allowed the observation of [2-13C]acetylcarnitine in vivo at 21.5 ppm, with a metabolic turnover time τ of 0.34 μmol/g/hr. The acetylcarnitine resonance assignment was confirmed by experiments infusing 13C labeled glucose. The measurement of the time courses of Glu C4 and C3 were also clearly observed, without lipid contamination. To conclude, this work presents novel metabolic information about skeletal and cardiac energy metabolism using developed methods in hyperpolarized 13C MRS. The use of hyperpolarized 13C substrates to measure absolute flux through metabolic pathways in vivo would not only revolutionize clinical diagnostic imaging but also serve as an important tool to better understand diseased metabolism and the metabolic effects of new drugs aimed to combat diseases.Lausanne, EPFL, 2013.
DOI : 10.5075/epfl-thesis-5969.
In Vivo Magnetic Resonance Spectroscopy (MRS) of the Activated Human Brain at 7T
The principal aim of this thesis was to investigate human brain energy metabolism during physiological activation using proton (1H) magnetic resonance spectroscopy (MRS) at 7 Tesla (T). High magnetic fields (≥ 7 T) provide several advantages in human brain imaging and spectroscopy. In particular, signal-to-noise ratio (SNR) and chemical shift dispersion increase at higher magnetic fields, allowing for improved accuracy and precision of metabolite quantification. To take profit of the benefits of MRS at high field, one needs to provide an advanced methodology including hardware, pulse sequences experimental setup and data analysis. Each of these aspects was thoroughly explored in this thesis. In the field of functional studies, functional MRS (fMRS) has recently been used as a research tool to investigate the neuroenergetic and metabolic basis of physiologic brain activation. It provides direct insight into brain metabolism by non-invasively determining concentrations of metabolites. This is critical for the basic understanding of overall brain function, and potentially of the pathogenesis of many neurodegenerative diseases. In general, an optimized MR system and accurate acquisition methodology are required for high sensitivity and reliable metabolite quantification. The metabolites of interest for fMRS studies (e.g. lactate, glucose) are present in low concentration and metabolite changes are small under activation. Hence, studies of metabolite changes, in particular lactate, have led to inconsistent reports in the literature over the last decades. To address these challenges, it was essential to develop a robust MR protocol for the quantitative measurement of metabolite changes. A fMRS study was performed to investigate metabolite changes during visual stimulation using the enhanced sensitivity of the SPin ECho full Intensity Acquired Localized (SPECIAL) sequence. Small but significant increases of lactate (19 ± 4 %, P < 0.05) and glutamate (4 ± 1 %, P < 0.001) were observed using a small number of subjects (n = 6). With the exception of glucose (12 ± 5 %, P < 0.001), no other significant metabolite concentration changes beyond experimental error were observed. Based on this successful fMRS study, we further investigated brain energy metabolism. A subsequent fMRS study was performed to determine metabolite changes occurring during motor activation in the human brain. This second study demonstrated that increases in lactate (17 ± 5 %, P < 0.001) and glutamate (2 ± 1 %, P < 0.005) during motor stimulation were small, but similar to those observed during visual stimulation. These metabolite changes were further analyzed, and they supported the hypothesis of an increase in the change of cerebral metabolic rate of oxygen, ∆CMRO2, that is transiently lower than that of glucose, ∆CMRGlc, during the first one to two minutes of stimulation. Finally, we hypothesized that the observed glutamate and lactate increases were a general manifestation of the blood-oxygenation level dependent effect. The accuracy and the reliability of metabolite quantification is particularly challenging at short echo times due to the presence of broad underlying resonances overlapping with those of metabolite. Such resonances arise from macromolecules, which are characterized by short T1 and T2 relaxation times. Two studies were performed at 3 T and 7 T to investigate the characteristics of the macromolecule signal. An important finding was that the mathematical approximation (spline baseline) was a sufficient estimation of the macromolecule contribution to 1H spectra at 3 T compared to the experimentally measured macromolecule signal for healthy subjects. As a caveat, small, but significant, differences in the quantification may need to be taken into account when comparing metabolite concentrations obtained with these two different approaches, such as for glutamate and for γ-amino-butyric, which were more reliably quantified when using the measured macromolecule baseline. In addition, a study on the tissue-specificity of the macromolecule signal in the healthy human occipital lobe at 7 T reported that a general average macromolecule signal ensured reliable metabolite quantification. In general, these studies helped to set up a robust and reliable methodology in order to investigate human brain metabolism with improved accuracy. Despite their great potential for MRS, high main magnetic fields also compose challenges. In particular, the wavelength of the proton spin resonance becomes comparable to the size of a human head (at 7 T, λ = 11 cm). The phase variation across the brain produces signal addition (constructive interference, central bright spot) and signal cancellation (destructive interference, signal drop). Transceive arrays have been developed to address this issue. In this study, we designed, tested, and built an eight-channel transceive array, which was used to acquire images of the human head at 7 T (297 MHz). The design aimed for a low mutual coupling between the microstrip elements (> -15 dB), a relatively large penetration depth in the loading sample, reduced radiation losses and load-invariant tuning and matching. Electromagnetic simulations were run using Microwave Studio (CST, Darmstadt, Germany) for design optimization. The model was further demonstrated with the construction of the transceive array. Finally, the resulting array coil was shown to be handling, stable and also suited for techniques in which the transmission signals from all channels with different amplitudes and phases are combined. To conclude, this thesis provided complementary and new metabolic information about cerebral energy metabolism during physiological activation. Furthermore, the macromolecule studies and the building of the transceive array allowed to improve the accuracy and sensitivity of NMR measurements.Lausanne, EPFL, 2013.
DOI : 10.5075/epfl-thesis-5943.
Lactate brain metabolism in different mouse strains probed by hyperpolarized 13C MRS
Lactate plays an important role in brain energetics and is essential for neuronal function. Alteration of its metabolism might be associated with mechanisms linked to neurodegenerative disorders1. The purpose of this study was to demonstrate the potential of of hyperpolarized [1-13C] lactate to sudy brain metabolism in mice. Following injection, hyperpolarized [1-13C] lactate is transferred through the blood brain barrier (BBB) via monocarboxylate transporters (MCTs), in particular MCT12. These transporters are thought to play an important role in neurodegenerative diseases but their concentration in different mice strains is not understood well. We performed real-time 13C metabolic studies with hyperpolarized [1-13C] lactate in two different mouse strains, namely NMRI mouse and C57BL/6. We could readily detect the signals of [1-13C] pyruvate, [1-13C] alanine and 13C bicarbonate. We observed a significant difference in the dynamics of lactate to pyruvate conversion between the two mouse strains. This demonstrates that the kinetics of lactate transport across the BBB is not identical in all mice strains and care should be taken when comparing metabolic processes between different animal types and in particular genetically modified strains used to study neurodegenerative disorders.4th International DNP Symposium, Copenhagen, Denmark, August 28-31, 2013.
Hyperpolarized [1-13C]lactate metabolism in rat skeletal muscle in vivo2013. 4th International DNP Symposium , Elsinore, Denmark , August 28-31, 2013.
Direct mapping of FDG uptake in situ at subcellular resolution using soft X-ray fluorescence2013. International Conference on Brain Energy Metabolism - Bioenergetics of Neurological Disease and Aging , Pacific Grove, CA , APR 17-20, 2012. p. 1106-1107.
Metabolism of [1,6-C-13]glucose in glutamatergic and GABAergic compartments in vivo in the rat brain2013. 10th International Conference on Brain Energy Metabolism - Bioenergetics of Neurological Disease and Aging , Pacific Grove, CA , APR 17-20, 2012. p. 1102.
Studying effects of glucose transporter isoform 2 on brain metabolic activities using localized H-1 MRS and perfusion MRI2013. 10th International Conference on Brain Energy Metabolism - Bioenergetics of Neurological Disease and Aging Location , Pacific Grove, CA , APR 17-20, 2012. p. 1104-1105.
MAGNETIC RESONANCE AND BIOLUMINESCENCE IMAGING MONITOR QUANTITATIVE DIFFERENCES IN PANCREATIC ISLETS AND THEIR REGENERATION AFTER BETA CELL LOSS2013. Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) , Boston, MA , APR 20-24, 2013. p. 531.2.
The C57BL/6J Mouse Exhibits Sporadic Congenital Portosystemic Shunts
C57BL/6 mice are the most widely used strain of laboratory mice. Using <italic>in vivo</italic> proton Magnetic Resonance Spectroscopy (<sup>1</sup>H MRS), we have repeatedly observed an abnormal neurochemical profile in the brains of both wild-type and genetically modified mice derived from the C57BL/6J strain, consisting of a several fold increase in cerebral glutamine and two fold decrease in myo-inositol. This strikingly abnormal neurochemical “phenotype” resembles that observed in chronic liver disease or portosystemic shunting and appeared to be independent of transgene, origin or chow and was not associated with liver failure. As many as 25% of animals displayed the abnormal neurochemical profile, questioning the reliability of this model for neurobiology. We conducted an independent study to determine if this neurochemical profile was associated with portosystemic shunting. Our results showed that 100% of the mice with high brain glutamine displayed portosystemic shunting by concomitant portal angiography while all mice with normal brain glutamine did not. Since portosystemic shunting is known to cause alterations in gene expression in many organs including the brain, we conclude that portosystemic shunting may be the most significant problem associated with C57BL/6J inbreeding both for its effect on the central nervous system and for its systemic repercussions.
DOI : 10.1371/journal.pone.0069782
New Developments and Applications of the MP2RAGE Sequence - Focusing the Contrast and High Spatial Resolution R1 Mapping
MR structural T1-weighted imaging using high field systems (>3T) is severely hampered by the existing large transmit field inhomogeneities. New sequences have been developed to better cope with such nuisances. In this work we show the potential of a recently proposed sequence, the MP2RAGE, to obtain improved grey white matter contrast with respect to conventional T1-w protocols, allowing for a better visualization of thalamic nuclei and different white matter bundles in the brain stem. Furthermore, the possibility to obtain high spatial resolution (0.65 mm isotropic) R1 maps fully independent of the transmit field inhomogeneities in clinical acceptable time is demonstrated. In this high resolution R1 maps it was possible to clearly observe varying properties of cortical grey matter throughout the cortex and observe different hippocampus fields with variations of intensity that correlate with known myelin concentration variations.
DOI : 10.1371/journal.pone.0069294
Improved off-resonance phase behaviour using a phase-inverted adiabatic half passage pulse for 13C NMR spectroscopy in humans at 7T2013. 30th Annual Scientific Meeting of the European Society of Magnetic Resonance in Medicine and Biology (ESMRMB) , Toulouse, FRANCE , October 3-5, 2013.
Brain metabolism in rat model of human glioma initiating cells2013. International Society for Magnetic Resonance in Medicine , Salt Lake City, USA , April 2013.
Glutamatergic and GABAergic energy metabolism measured in the rat brain by 13C NMR spectroscopy at 14.1 T
Energy metabolism supports both inhibitory and excitatory neurotransmission processes. This study investigated the specific contribution of astrocytic metabolism to γ-aminobutyric acid (GABA) synthesis and inhibitory GABAergic neurotransmission that remained to be ilucidated in vivo. Therefore we measured 13C incorporation into brain metabolites by dynamic 13C nuclear magnetic resonance spectroscopy at 14.1 T in rats under α-chloralose anaesthesia during infusion of [1,6-13C]glucose. The enhanced sensitivity at 14.1 T allowed to quantify incorporation of 13C into the three aliphatic carbons of GABA non-invasively. Metabolic fluxes were determined with a mathematical model of brain metabolism comprising glial, glutamatergic and GABAergic compartments. GABA synthesis rate was 0.11±0.01 μmol/g/min. GABA-glutamine cycle was 0.053±0.003 μmol/g/min and accounted for 22±1% of total neurotransmitter cycling between neurons and glia. Cerebral glucose oxidation was 0.47±0.02 μmol/g/min, of which 35±1% and 7±1% was diverted to the glutamatergic and GABAergic tricarboxylic acid cycles, respectively. The remaining fraction of glucose oxidation was in glia, where 12±1% of the TCA cycle flux was dedicated to oxidation of GABA. 16±2% of glutamine synthesis was provided to GABAergic neurons. We conclude that substantial metabolic activity occurs in GABAergic neurons and that glial metabolism supports both glutamatergic and GABAergic neurons in the living rat brain. This article is protected by copyright. All rights reserved.
Journal of Neurochemistry
DOI : 10.1111/jnc.12333
Hyperpolarized [1-13C]acetylcarnitine as a tracer for cardiac metabolism2013. International Society for Magnetic Resonance in Medicine , Salt Lake City, USA , April 2013. p. 1936.
Acetylcarnitine turnover in rat skeletal muscle measured in vivo using localized 13C NMR at 14.1 T2013. International Society for Magnetic Resonance in Medicine , Salt Lake City, USA , April 2013. p. 120.
Unedited in vivo detection and quantification of gamma-aminobutyric acid in the occipital cortex using short-TE MRS at 3 T
Short-TE MRS has been proposed recently as a method for the in vivo detection and quantification of gamma-aminobutyric acid (GABA) in the human brain at 3 T. In this study, we investigated the accuracy and reproducibility of short-TE MRS measurements of GABA at 3 T using both simulations and experiments. LCModel analysis was performed on a large number of simulated spectra with known metabolite input concentrations. Simulated spectra were generated using a range of spectral linewidths and signal-to-noise ratios to investigate the effect of varying experimental conditions, and analyses were performed using two different baseline models to investigate the effect of an inaccurate baseline model on GABA quantification. The results of these analyses indicated that, under experimental conditions corresponding to those typically observed in the occipital cortex, GABA concentration estimates are reproducible (mean reproducibility error, <20%), even when an incorrect baseline model is used. However, simulations indicate that the accuracy of GABA concentration estimates depends strongly on the experimental conditions (linewidth and signal-to-noise ratio). In addition to simulations, in vivo GABA measurements were performed using both spectral editing and short-TE MRS in the occipital cortex of 14 healthy volunteers. Short-TE MRS measurements of GABA exhibited a significant positive correlation with edited GABA measurements (R = 0.58, p < 0.05), suggesting that short-TE measurements of GABA correspond well with measurements made using spectral editing techniques. Finally, within-session reproducibility was assessed in the same 14 subjects using four consecutive short-TE GABA measurements in the occipital cortex. Across all subjects, the average coefficient of variation of these four GABA measurements was 8.7 /- 4.9%. This study demonstrates that, under some experimental conditions, short-TE MRS can be employed for the reproducible detection of GABA at 3 T, but that the technique should be used with caution, as the results are dependent on the experimental conditions. Copyright (c) 2013 John Wiley & Sons, Ltd.
NMR in Biomedicine
DOI : 10.1002/nbm.2960
The C57BL/6 mouse exhibits sporadic congenital portosystemic shuntsISMRM.
In vivo and longitudinal assessment of brain metabolism in Hepatic Encephalopathy using 1H MRSISMRM.
FatNavs: Exploiting the Natural Sparsity of Head Fat Images for High-Resolution Motion-Navigation at Very High Acceleration Factors2013. 21st Annual Meeting of the ISMRM , Salt Lake City, Utah, USA , April 2013. p. 309.
In Vivo 1H MRS at 14.1T for the Accurate Characterization of the Lipid Profile of the Mouse Liver
1H MRS was employed at 14.1T to non-invasively quantify the lipid content of small samples (8-15 µl). In the mouse liver, good spectral stability was achieved by running individual scans within one breathing cycle. Ultra short TE STEAM with water suppression was used to estimate the unsaturation profile of the fatty acyl chains. This method was in good agreement with in vitro measurements in phantoms. High field is advantageous to accurately characterize the lipid profile of small samples such as the volumes selected in the liver of mice, with no need to increase the acquisition time for sensitivity gain.ISMRM 21st Annual Meeting & Exhibition, Salt Lake City, Utah, USA, 20-26 April 2013.
Evolution of the Hepatic Lipid Profile of the Adult Mouse - in Vivo and in Vitro 1H MRS Assessments at 14.1T
The hepatic lipid content and composition were assessed in healthy mice throughout adulthood. It was found that aging and obesity contributed to increase the amount of lipids in the liver while decreasing the poly-unsaturation degree. The combination of in vivo 1H MRS assessments with in vitromeasurements on tissues extracts illustrated the important contribution of membrane lipids to the total poly-unsaturation degree of the fatty acyl chains. Changes of the unsaturation profile of cytosolic lipids can be monitored by in vivo 1H MRS, which is of interest for the study of genetic and diet-induced mice models of metabolic diseases.ISMRM 21st Annual Meeting & Exhibition, Salt Lake City, Utah, USA, 20-26 April 2013.
Superior GRAPPA reconstruction with reduced g-factor noise using 2D CAIPIRINHA for 3D EPI
Efficient GRAPPA or SENSE reconstruction is largely dependent on coil geometry in the direction in which phase encoding steps reduction is performed during partially parallel acquisition. In this study we demonstrate the ability to perform a 2D CAIPIRINHA trajectory in a 3D EPI sequence to reduce the geometry factor (g-factor) noise amplification in the reconstructed images for a predefined total acceleration. 2D CAIPIRINHA style k-space patterns provide improved reconstructions when using very large accelerations on one phase-encode direction, thanks to the ability to use the coil sensitivities along the other phase-encode direction to compensate the reduced coil sensitivity variation.2013. ISMRM 21st Annual Meeting & Exhibition , Salt Lake City, Utah, USA , April 20-26, 2013.
Metabolite concentration changes during motor activation using functional Magnetic Resonance Spectroscopy (fMRS) at 7T
Functional MR spectroscopy (fMRS) allows to investigate the metabolic response of the brain to a physiological stimulation, by acquiring continuously MR spectra during a functional task, and provides direct insights into brain metabolism. For the studies of dynamic concentration changes using fMRS, a high time evolution is of advantage for the characterization of the very small transient changes (around 0.2μmol/g). Therefore, measurements with the highest sensitivity are desirable. Recent studies at high field (7 Tesla) reported small metabolite concentration changes (around 0.2µmol/g) and in particular a lactate concentration increase varying between 10-23% during visual stimulation. Additionally, it is interesting to investigate metabolite changes during other stimulation. Therefore, the aim of this study was to investigate the metabolite changes during motor activation in the human brain and to compare these changes with those of visual activation.2013. 21st Annual Meeting of the International Society of Magnetir Resonance in Medicine (ISMRM) , Salt Lake City , April 20-27, 2013.
Extended neurochemical profile in the aging mouse brain detected in vivo by proton magnetic resonance spectroscopy2013. 24th Biennial Meeting of the International-Society-for-Neurochemistry and the American-Society-for-Neurochemistry , Cancun, MEXICO , APR 20-24, 2013. p. 244-244.
The C57BL/6 mouse exhibits sporadic congenital portosystemic shunts2013. 24th Biennial Meeting of the International-Society-for-Neurochemistry and the American-Society-for-Neurochemistry , Cancun, MEXICO , APR 20-24, 2013. p. 107-108.
Measurement of long stimulation paradigms with BOLD fMRI in the rat brain for compartmentalized metabolism study2013. 24th Biennial Meeting of the International-Society-for-Neurochemistry and the American-Society-for-Neurochemistry , Cancun, MEXICO , APR 20-24, 2013. p. 279-279.
Diffusion MRI study of slowly growing human glioma models in mice at 14.1T2013. ISMRM 21st Annual Meeting &Exhibition , Salt Lake City, Utah, USA , April 20-26, 2013. p. 1063.
3D Residual Eddy Current Field Characterisation: applied to Diffusion Weighted Magnetic Resonance Imaging
Clinical use of the Stejskal-Tanner diffusion weighted images is hampered by the geometric distortions that result from the large residual 3D eddy current field induced. In this work we aimed to predict, using linear response theory, the residual 3D eddy current field required for geometric distortion correction based on phantom eddy current field measurements. The predicted 3D eddy current field induced by the diffusion-weighting gradients was able to reduce the root mean square error of the residual eddy current field to ~1Hz. The model’s performance was tested on diffusion weighted images of 4 normal volunteers, following distortion correction, the image quality of the Stejskal-Tanner diffusion-weighted images was found to have comparable image quality to image registration based corrections (FSL) at low b-values. Unlike registration techniques the correction was not hindered by low SNR at high b-values, and results in improved image quality relative to FSL. Characterization of the 3D eddy current field with linear response theory enables the prediction of the 3D eddy current field required to correct eddy current induced geometric distortions for a wide range of clinical and high b-value protocols.
IEEE Transactions on Medical Imaging
DOI : 10.1109/TMI.2013.2259249
Single spin-echo T 2 relaxation times of cerebral metabolites at 14.1 T in the in vivo rat brain
OBJECT: To determine the single spin-echo T 2 relaxation times of uncoupled and J-coupled metabolites in rat brain in vivo at 14.1 T and to compare these results with those previously obtained at 9.4 T. MATERIALS AND METHODS: Measurements were performed on five rats at 14.1 T using the SPECIAL sequence and TE-specific basis-sets for LCModel analysis. RESULTS AND CONCLUSION: The T 2 of singlets ranged from 98 to 148 ms and T 2 of J-coupled metabolites ranged from 72 ms (glutamate) to 97 ms (myo-inositol). When comparing the T 2s of the metabolites measured at 14.1 T with those previously measured at 9.4 T, a decreasing trend was found (p < 0.0001). We conclude that the modest shortening of T 2 at 14.1 T has a negligible impact on the sensitivity of the (1)H MRS when performed at TE shorter than 10 ms.
Magma (New York, N.Y.)
DOI : 10.1007/s10334-013-0378-3
Hepatic glucose sensing is required to preserve β cell glucose competence
Liver glucose metabolism plays a central role in glucose homeostasis and may also regulate feeding and energy expenditure. Here we assessed the impact of glucose transporter 2 (Glut2) gene inactivation in adult mouse liver (LG2KO mice). Loss of Glut2 suppressed hepatic glucose uptake but not glucose output. In the fasted state, expression of carbohydrate-responsive element-binding protein (ChREBP) and its glycolytic and lipogenic target genes was abnormally elevated. Feeding, energy expenditure, and insulin sensitivity were identical in LG2KO and control mice. Glucose tolerance was initially normal after Glut2 inactivation, but LG2KO mice exhibited progressive impairment of glucose-stimulated insulin secretion even though β cell mass and insulin content remained normal. Liver transcript profiling revealed a coordinated downregulation of cholesterol biosynthesis genes in LG2KO mice that was associated with reduced hepatic cholesterol in fasted mice and reduced bile acids (BAs) in feces, with a similar trend in plasma. We showed that chronic BAs or farnesoid X receptor (FXR) agonist treatment of primary islets increases glucose-stimulated insulin secretion, an effect not seen in islets from Fxr-/- mice. Collectively, our data show that glucose sensing by the liver controls β cell glucose competence and suggest BAs as a potential mechanistic link.
The Journal of clinical investigation
DOI : 10.1172/JCI65538
An improved surface coil design for proton decoupled Carbon-13 Magnetic Resonance Spectroscopy2013. 21th Annual meeting of the International Society for Magnetic Resonance in Medicine (ISMRM) , Salt Lake City, Utah, USA , April 20-26, 2013.
In vivo enzymatic activity of acetylCoA synthetase in skeletal muscle revealed by (13)C turnover from hyperpolarized [1-(13)C]acetate to [1-(13)C]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 one minute. 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 modelling 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 ± 0.13 mM and Vmax = 0.198 ± 0.030 μmol/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.
Biochimica et biophysica acta
DOI : 10.1016/j.bbagen.2013.03.023
Investigation of field and diffusion time dependence of the diffusion-weighted signal at ultrahigh magnetic fields
Over the last decade, there has been a significant increase in the number of high-magnetic-field MRI magnets. However, the exact effect of a high magnetic field strength (B0 ) on diffusion-weighted MR signals is not yet fully understood. The goal of this study was to investigate the influence of different high magnetic field strengths (9.4 T and 14.1 T) and diffusion times (9, 11, 13, 15, 17 and 24 ms) on the diffusion-weighted signal in rat brain white matter. At a short diffusion time (9 ms), fractional anisotropy values were found to be lower at 14.1 T than at 9.4 T, but this difference disappeared at longer diffusion times. A simple two-pool model was used to explain these findings. The model describes the white matter as a first hindered compartment (often associated with the extra-axonal space), characterized by a faster orthogonal diffusion and a lower fractional anisotropy, and a second restricted compartment (often associated with the intra-axonal space), characterized by a slower orthogonal diffusion (i.e. orthogonal to the axon direction) and a higher fractional anisotropy. Apparent T2 relaxation time measurements of the hindered and restricted pools were performed. The shortening of the pseudo-T2 value from the restricted compartment with B0 is likely to be more pronounced than the apparent T2 changes in the hindered compartment. This study suggests that the observed differences in diffusion tensor imaging parameters between the two magnetic field strengths at short diffusion time may be related to differences in the apparent T2 values between the pools. Copyright © 2013 John Wiley & Sons, Ltd.
NMR in biomedicine
DOI : 10.1002/nbm.2945
9.4-14.1 T small-animal PET-MR imaging: Feasibility analysis of LYSO APD readout via long signal lines
In the present work we intend to assess the readout feasibility of Avalanche Photodiode (APD) detectors via long signal lines for the development of a combined small-animal PET-MR prototype based on the ClearPEM technology. The detection performance of a LYSO-APD module was evaluated reading out the APD charge signals to the front-end ASIC via an 80 mm length flexible flat-cable (FFC). Experimental results showed a time resolution of 5.06 ns for the detector module in double-readout mode, with a nonsignificant degradation of 8.4% with the introduction of the FFC. The energy resolution of the system was not degradated by the FFC. (C) 2012 Elsevier B.V. All rights reserved.
Nuclear Instruments & Methods In Physics Research Section A-Accelerators Spectrometers Detectors And Associated Equipment
DOI : 10.1016/j.nima.2012.08.032
Feasibility and electromagnetic compatibility study of the ClearPEM front-end electronics for simultaneous PET-MR imaging
In this work we present a first feasibility study of the ClearPEM technology for simultaneous PET-MR imaging. The mutual electromagnetic interference (EMI) effects between both systems were evaluated on a 7 T magnet by characterizing the response behavior of the ClearPEM detectors and front-end electronics to pulsed RF power and switched magnetic field gradients; and by analyzing the MR system performance degradation from noise pickup into the RF receiver chain, and from magnetic susceptibility artifacts caused by PET front-end materials.
Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment
DOI : 10.1016/j.nima.2012.08.033
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 1H-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 metabolites concentrations as well as low concentrations of the metabolites of interest such as (lactate (Lac), glucose (Glc) or gamma-amminobutyric 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 ( 1.01mumol/g, p<0.008) and glutamate ( 0.92mumol/g, p<0.02) and significant negative aspartate changes (-0.63mumol/g, p<0.004) using functional 1HMRS at 9.4T 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.
DOI : 10.1016/j.neuroimage.2013.02.042
Quantification of the neurochemical profile using simulated macromolecule resonances at 3 T
The broad resonances underlying the entire (1) H NMR spectrum of the brain, ascribed to macromolecules, can influence metabolite quantification. At the intermediate field strength of 3 T, distinct approaches for the determination of the macromolecule signal, previously used at either 1.5 or 7 T and higher, may become equivalent. The aim of this study was to evaluate, at 3 T for healthy subjects using LCModel, the impact on the metabolite quantification of two different macromolecule approaches: (i) experimentally measured macromolecules; and (ii) mathematically estimated macromolecules. Although small, but significant, differences in metabolite quantification (up to 23% for glutamate) were noted for some metabolites, 10 metabolites were quantified reproducibly with both approaches with a Cramer-Rao lower bound below 20%, and the neurochemical profiles were therefore similar. We conclude that the mathematical approximation can provide sufficiently accurate and reproducible estimation of the macromolecule contribution to the (1) H spectrum at 3 T. Copyright © 2013 John Wiley & Sons, Ltd.
NMR in biomedicine
DOI : 10.1002/nbm.2896
Net increase of lactate and glutamate concentration in activated human visual cortex detected with magnetic resonance spectroscopy at 7 tesla
After the landmark studies reporting changes in the cerebral metabolic rate of glucose (CMR(Glc) ) in excess of those in oxygen (CMR(O2) ) during physiological stimulation, several studies have examined the fate of the extra carbon taken up by the brain, reporting a wide range of changes in brain lactate from 20% to 250%. The present study reports functional magnetic resonance spectroscopy measurements at 7 Tesla using the enhanced sensitivity to study a small cohort (n = 6). Small increases in lactate (19% ± 4%, P < 0.05) and glutamate (4% ± 1%, P < 0.001) were seen within the first 2 min of activation. With the exception of glucose (12% ± 5%, P < 0.001), no other metabolite concentration changes beyond experimental error were significantly observed. Therefore, the present study confirms that lactate and glutamate changes during physiological stimulation are small (i.e. below 20%) and shows that the increased sensitivity allows reproduction of previous results with fewer subjects. In addition, the initial rate of glutamate and lactate concentration increases implies an increase in CMR(O2) that is slightly below that of CMR(Glc) during the first 1-2 min of activation. © 2013 Wiley Periodicals, Inc.
Journal of neuroscience research
DOI : 10.1002/jnr.23194
Feasibility of direct mapping of cerebral fluorodeoxy-D-glucose metabolism in situ at subcellular resolution using soft X-ray fluorescence
Glucose metabolism is difficult to image with cellular resolution in mammalian brain tissue, particularly with (18) fluorodeoxy-D-glucose (FDG) positron emission tomography (PET). To this end, we explored the potential of synchrotron-based low-energy X-ray fluorescence (LEXRF) to image the stable isotope of fluorine (F) in phosphorylated FDG (DG-6P) at 1 μm(2) spatial resolution in 3-μm-thick brain slices. The excitation-dependent fluorescence F signal at 676 eV varied linearly with FDG concentration between 0.5 and 10 mM, whereas the endogenous background F signal was undetectable in brain. To validate LEXRF mapping of fluorine, FDG was administered in vitro and in vivo, and the fluorine LEXRF signal from intracellular trapped FDG-6P over selected brain areas rich in radial glia was spectrally quantitated at 1 μm(2) resolution. The subsequent generation of spatial LEXRF maps of F reproduced the expected localization and gradients of glucose metabolism in retinal Müller glia. In addition, FDG uptake was localized to periventricular hypothalamic tanycytes, whose morphological features were imaged simultaneously by X-ray absorption. We conclude that the high specificity of photon emission from F and its spatial mapping at ≤1 μm resolution demonstrates the ability to identify glucose uptake at subcellular resolution and holds remarkable potential for imaging glucose metabolism in biological tissue. © 2012 Wiley Periodicals, Inc.
Journal of neuroscience research
DOI : 10.1002/jnr.23171
Digit somatotopy in the human cerebellum: A 7T fMRI study
The representation of the human body in the human cerebellum is still relatively unknown, compared to the well-studied homunculus in the primary somatosensory cortex. The investigation of the body representation in the cerebellum and its somatotopic organisation is complicated because of the relatively small dimensions of the cerebellum, compared to the cerebrum. Somatotopically organised whole-body homunculi have previously been reported in both humans and rats. However, whether individual digits are represented in the cerebellum in a somatotopically organised way is much less clear. In this study, the high spatial resolution and high sensitivity to the blood oxygenation level dependent (BOLD) signal of 7T fMRI were employed to study the BOLD responses in the human cerebellum to the stroking of the skin of individual digits, the hand and forearm. For the first time, a coarse somatotopic organisation of the digits, ordered from D1-D5, could be visualised in individual human subjects in both the anterior (lobule V) and the posterior (lobule VIII) lobes of the cerebellum using a somatosensory stimulus. The somatotopic gradient in lobule V was found consistently in the posterior to anterior direction, with the thumb most posterior, while the direction of the somatotopic gradient in lobule VIII differed between subjects. No somatotopic organisation was found in Crus I. A comparison of the digit patches with the hand patch revealed that the digit regions are completely covered by the hand region in both the anterior and posterior lobes of the cerebellum, in a non-somatotopic manner. These results demonstrate the promise of ultra-high field, high-resolution fMRI for studies of the cerebellum.
DOI : 10.1016/j.neuroimage.2012.11.041
Proton T(1) relaxation times of metabolites in human occipital white and gray matter at 7 T
Proton T(1) relaxation times of metabolites in the human brain have not previously been published at 7 T. In this study, T(1) values of CH(3) and CH(2) group of N-acetylaspartate and total creatine as well as nine other brain metabolites were measured in occipital white matter and gray matter at 7 T using an inversion-recovery technique combined with a newly implemented semi-adiabatic spin-echo full-intensity acquired localized spectroscopy sequence (echo time = 12 ms). The mean T(1) values of metabolites in occipital white matter and gray matter ranged from 0.9 to 2.2 s. Among them, the T(1) of glutathione, scyllo-inositol, taurine, phosphorylethanolamine, and N-acetylaspartylglutamate were determined for the first time in the human brain. Significant differences in T(1) between white matter and gray matter were found for water (-28%), total choline (-14%), N-acetylaspartylglutamate (-29%), N-acetylaspartate ( 4%), and glutamate ( 8%). An increasing trend in T(1) was observed when compared with previously reported values of N-acetylaspartate (CH(3) ), total creatine (CH(3) ), and total choline at 3 T. However, for N-acetylaspartate (CH(3) ), total creatine, and total choline, no substantial differences compared to previously reported values at 9.4 T were discernible. The T(1) values reported here will be useful for the quantification of metabolites and signal-to-noise optimization in human brain at 7 T. Magn Reson Med, 2012. © 2012 Wiley Periodicals, Inc.
Magnetic Resonance in Medicine
DOI : 10.1002/mrm.24352
An in vivo ultrahigh field 14.1 T (1) H-MRS study on 6-OHDA and α-synuclein-based rat models of Parkinson's disease: GABA as an early disease marker
The detection of Parkinson's disease (PD) in its preclinical stages prior to outright neurodegeneration is essential to the development of neuroprotective therapies and could reduce the number of misdiagnosed patients. However, early diagnosis is currently hampered by lack of reliable biomarkers. (1) H magnetic resonance spectroscopy (MRS) offers a noninvasive measure of brain metabolite levels that allows the identification of such potential biomarkers. This study aimed at using MRS on an ultrahigh field 14.1 T magnet to explore the striatal metabolic changes occurring in two different rat models of the disease. Rats lesioned by the injection of 6-hydroxydopamine (6-OHDA) in the medial-forebrain bundle were used to model a complete nigrostriatal lesion while a genetic model based on the nigral injection of an adeno-associated viral (AAV) vector coding for the human α-synuclein was used to model a progressive neurodegeneration and dopaminergic neuron dysfunction, thereby replicating conditions closer to early pathological stages of PD. MRS measurements in the striatum of the 6-OHDA rats revealed significant decreases in glutamate and N-acetyl-aspartate levels and a significant increase in GABA level in the ipsilateral hemisphere compared with the contralateral one, while the αSyn overexpressing rats showed a significant increase in the GABA striatal level only. Therefore, we conclude that MRS measurements of striatal GABA levels could allow for the detection of early nigrostriatal defects prior to outright neurodegeneration and, as such, offers great potential as a sensitive biomarker of presymptomatic PD. Copyright © 2012 John Wiley & Sons, Ltd.
NMR in biomedicine
DOI : 10.1002/nbm.2817
Which prior knowledge? Quantification of in vivo brain (13) C MR spectra following (13) C glucose infusion using AMARES
The recent developments in high magnetic field (13) C magnetic resonance spectroscopy with improved localization and shimming techniques have led to important gains in sensitivity and spectral resolution of (13) C in vivo spectra in the rodent brain, enabling the separation of several (13) C isotopomers of glutamate and glutamine. In this context, the assumptions used in spectral quantification might have a significant impact on the determination of the (13) C concentrations and the related metabolic fluxes. In this study, the time domain spectral quantification algorithm AMARES (advanced method for accurate, robust and efficient spectral fitting) was applied to (13) C magnetic resonance spectroscopy spectra acquired in the rat brain at 9.4 T, following infusion of [1,6-(13) C(2) ] glucose. Using both Monte Carlo simulations and in vivo data, the goal of this work was: (1) to validate the quantification of in vivo (13) C isotopomers using AMARES; (2) to assess the impact of the prior knowledge on the quantification of in vivo (13) C isotopomers using AMARES; (3) to compare AMARES and LCModel (linear combination of model spectra) for the quantification of in vivo (13) C spectra. AMARES led to accurate and reliable (13) C spectral quantification similar to those obtained using LCModel, when the frequency shifts, J-coupling constants and phase patterns of the different (13) C isotopomers were included as prior knowledge in the analysis. Magn Reson Med, 2012. © 2012 Wiley Periodicals, Inc.
Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine
DOI : 10.1002/mrm.24406
Description of a mouse model of peripheral artery disease to investigate exercise training as a therapeutic strategy.2012. p. FM1.
The influence of frontal glutathione levels on white matter connectivity in healthy and early psychosis subjects: a preliminary study2012. ESMRMB - European Society for Magnetic Resonance in Medicine and Biology , Lisbon, Portugal .
In vivo longitudinal 1H Spectroscopic Imaging and Diffusion Tensor Imaging studies at 9.4T in a rat model of chronic liver failureISMRM 20th Annual Scientific Meeting, 5-11 May 2012, Melbourne, Australia.
Brain osmolytes and brain edema in a rat model of chronic liver failure: in vivo longitudinal 1H Spectroscopic imaging and Diffusion tensor imaging studies at 9.4TThe 15th International Society of Hepatic Encephalopathy and Nitrogen Metabolism, Symposium May 29 - June 2, 2012, Denmark.
Metabolism of [1,6-C-13] glucose in glutamatergic and GABAergic compartments in vivo in the rat brain2012. 22nd IUBMB Congress/37th FEBS Congress . p. 369-369.
Mathematical Modeling of Brain Energy Metabolism, Measured with PET and MRS in Rodents
Positron emission tomography (PET) and nuclear magnetic resonance spectroscopy (MRS) are two biomedical measurement techniques developed in the end of the XXth century, which drastically improved the amount of accessible information available in vivo. PET became popular through the most widely used tracer, fluorodeoxyglucose (FDG), which enables the measurement of the local glucose utilization and is nowadays routinely applied in clinical practice. Nuclear magnetic resonance is used in a large array of applications such as in analytical chemistry or chemical structure determination and is essentially known for its versatile medical imaging capabilities, grouped under the name of magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). In vivo MRS measures concentrations of metabolites by interacting with various nuclei such as 1H, 13C or 15N, with the major asset that MRS enables the identification of the chemical position at which the detected nuclei is located in the measured molecule. When coupled with labeled substrate infusions, dynamic MRS gives the opportunity to probe specific biochemical reactions directly in vivo, which opens the way to a wide range of metabolic studies. However, the correct interpretation of the elaborate dynamic labeling data acquired either with MRS or PET tracer experiments requires the application of adapted metabolic models to derive quantitative metabolic rates characterizing the biochemical processes under study. The work of this thesis involves both PET and MRS studies of brain energy metabolism in rodents and focuses on the development of adapted metabolic models to derive reliable metabolic fluxes characterizing various brain metabolic processes, such as glucose consumption, glial and neuronal oxidative metabolism and neurotransmission. FDG-PET enables the measurement of the cerebral metabolic rate of glucose (CMRGlc) using a three-compartment metabolic model for FDG transport across the blood-brain barrier and FDG phosphorylation to FDG-6P. Although this method is well established, a main drawback of CMRGlc measurement with FDG-PET is the necessity to characterize the available FDG concentration in the plasma over the experiment duration, the so-called arterial input function. This constraint is a strong limitation for preclinical studies in rodents, due to their low blood volume. We developed therefore a new method to extract the FDG input function directly from the PET images in rats and mice, using the time-activity curve of a voxel located in the inferior vena cava. The method was validated by comparison with a dedicated external blood counter and manual blood sampling. Using this method, a CMRGlc of ~0.22 μmol/g/min was determined in the mouse cortex. Glial oxidative metabolism can be specifically assessed using glial specific substrates, in particular [1-11C] acetate. However, no existing metabolic model described the 11C tissue activity curve in terms of neuroglial energy metabolism. In order to extract quantitative metabolic fluxes characterizing the glial TCA cycle rate and glutamate/glutamine cycling, we adapted the neuroglial two-compartment modeling approach previously used in 13C MRS cerebral metabolic studies to interpret positron emission data following 11C-acetate injection in the rat. The precision and accuracy of the estimated metabolic parameters was tested and a composite glial metabolic flux Vgtg=0.136 ± 0.042 μmol/g/min and a neurotransmission flux Vnt=0.170 ± 0.103 μmol/g/min were obtained. This approach enabled a direct comparison of the metabolic fluxes measured using 11C PET with the values determined with 13C MRS. In the field of 13C MRS, we took advantage of the higher sensitivity and spectral resolution available at high magnetic field (14.1T) to measure glial and neuronal oxidative metabolism, glutamatergic neurotransmission and pyruvate carboxylation in more details and with higher precision using both [1,6-13C2] glucose and [2-13C] acetate infusions in rats. In the acetate study, the glial specific uptake of acetate enabled a quantification of glial oxidative metabolism with unrivalled precision. We could estimate for the first time separately the transmitochondrial flux Vx in the glial and neuronal compartment, a biochemical pathway which has been subject of strong controversy. The glial and neuronal Vx were determined with high precision, as calculated through Monte Carlo simulation, and their value was on the same order of magnitude than the respective glial and neuronal TCA cycle flux. The model was extended to estimate the fraction of glutamate located in the glial compartment. A glial glutamate concentration of 0.6 ± 0.1 μmol/g was found. The values of the different metabolic fluxes characterizing the neuroglial system (Vtcag=0.27, Vxg=0.17, VPC=0.087, VNT=0.15, Vtcan=0.37 and Vxn=0.46 μmol/g/min) were in very good agreement with the values found using [1,6-13C2] glucose infusion. In addition, the effect of the MRS temporal resolution, experiment duration and signal- to-noise ratio on the precision of the derived metabolic fluxes was analyzed. Previous simulation studies showed that two-compartment modeling of neuroglial metabolism using 13C glucose infusion could lead to unreliable parameter estimations. However, using polarization transfer 13C MRS at 14.1T, the carbon positions C4, C3 and C2 of glutamate and glutamine as well as the positions C3 and C2 of aspartate could be measured with high SNR. The C2 positions were used in two-compartment modeling for the first time, enabling a precise measurement of the apparent glutamatergic neurotransmission and glial metabolism, including pyruvate carboxylation, as confirmed by Monte Carlo simulation. The glial dilution at the level of acetyl-CoA, which is related to the metabolism of other substrates than glucose, could also be characterized. Brain metabolism under hyperammonemic conditions was probed with 15N MRS under labeled ammonia infusion and modeled using a modified neuroglial two- compartment model describing the dynamics of [5-15N] glutamine, [2-15N] glutamate and [2-15N] glutamine. Due to detoxification processes, the total glutamine concentration, measured with 1H MRS, was steadily increasing. This non-steady- state metabolic condition resulting from the hyperammonemic stress was taken into account in the model, resulting in the determination of the apparent neurotransmission (0.26 ± 0.030 μmol/g/min), the glutamate dehydrogenase (0.029 ± 0.002 μmol/g/min) and net glutamine accumulation (0.033 ± 0.001 μmol/g/min). Finally, compartmental modeling was applied to 13C labeling studies in the awake rat, fed during 5, 24 or 48 h with a [1-13C]-labeled glucose solution, to determine brain glycogen and NAA turnover times (τGlyc=5.3 ± 3.2 h and τNAA=15.6 ± 6.5 h), using 13C spectra of brain extracts. A group of rats followed a mild brain activation protocol over 5 hours, which resulted in a decreased glycogen turnover time (τGlyc =2.9 ± 1.2 h).Lausanne, EPFL, 2012.
DOI : 10.5075/epfl-thesis-5468.
Deletion of glutamate dehydrogenase 1 (Glud1) in the central nervous system affects glutamate handling without altering synaptic transmission
Glutamate dehydrogenase (GDH), encoded by GLUD1, participates in the breakdown and synthesis of glutamate, the main excitatory neurotransmitter. In the CNS, besides its primary signaling function, glutamate is also at the crossroad of metabolic and neurotransmitter pathways. Importance of brain GDH was questioned here by generation of CNS-specific GDH-null mice (CnsGlud1(-/-) ); which were viable, fertile and without apparent behavioral problems. GDH immunoreactivity as well as enzymatic activity were absent in Cns-Glud1(-/-) brains. Immunohistochemical analyses on brain sections revealed that the pyramidal cells of control animals were positive for GDH, whereas the labeling was absent in hippocampal sections of Cns-Glud1(-/-) mice. Electrophysiological recordings showed that deletion of GDH within the CNS did not alter synaptic transmission in standard conditions. Cns-Glud1(-/-) mice exhibited deficient oxidative catabolism of glutamate in astrocytes, showing that GDH is required for Krebs cycle pathway. As revealed by NMR studies, brain glutamate levels remained unchanged, whereas glutamine levels were increased. This pattern was favored by up-regulation of astrocyte-type glutamate and glutamine transporters and of glutamine synthetase. Present data show that the lack of GDH in the CNS modifies the metabolic handling of glutamate without altering synaptic transmission.
Journal of neurochemistry
DOI : 10.1111/j.1471-4159.2012.07933.x
GLUT2-/- mice are resistant to age-induced accumulation of fat in the liver – an in vivo MRS study
Introduction: Whole-body energy balance is strongly dependent on the hepatic handling of metabolic fuels, which is affected by the hepatic lipid content (HLC). With in vivo nuclear magnetic resonance spectroscopy (MRS) HLC can be measured non-invasively and longitudinally. The study of mice is relevant for the characterization of transgenic models that provide insight into disease mechanisms but comparing with bigger subjects, the reduced sample size remains a limiting factor for in vivo MRS experiments. To overcome this sensitivity issue, we performed liver MRS in vivo at high field (14.1T) in wild-type C57BL/6J mice (WT) and GLUT2-/- mice that display altered whole-body energy balance. Methods: WT and GLUT2-/- mice reexpressing GLUT1 in the pancreatic β-cells to allow for survival and normal glucose-stimulated insulin secretion were studied at 4 months and 1 year of age. Non-fasted mice under isofluorane anesthesia were scanned in the supine position with a 1H quadrature surface coil over the abdomen. MRS measurements were performed in a horizontal bore 14.1T-26 cm magnet. Multi-slice gradient echo images were acquired for anatomical identification of the liver. Localized, respiration-gated 1H-MR spectra were acquired from a 10-15 µl voxel with STEAM with and without water suppression. HLC was estimated as the T2-corrected area of 1.3 ppm-lipid resonance relative to that of the water plus 1.3 ppm-lipid. Results/Discussion: Highly sensitive MRS at 14.1T allowed to accurately quantifying HLC in short experiments in mice. Suppression of the water signal revealed fatty-acyl resonances reflecting the lipid saturation profile. At 4 months, HLC was similar between WT and GLUT2-/-. HLC increased significantly in aged WT mice but remained low in aged GLUT2-/-. Also, the body weight of aged GLUT2-/- was slightly lower than that of WT. Low HLC in aged GLUT2-/- mice probably results from a defect on intra-hepatic pathway fluxes due to GLUT2 ablation in the liver. In addition, it may reflect altered utilization of metabolic substrates due to inadequate whole-body blood glucose sensing.2012. 22nd Congress of the International Union of Biochemistry and Molecular Biology and 37th Congress of the Federation of European Biochemical Societies , Sevilla, Spain , September 4-9, 2012. p. 268-268.
Improved lipid profiling of the mouse liver by 1H-NMR spectroscopy at 14.1T in vivo
Purpose/Introduction: Whole-body metabolic deregulation features changes in hepatic lipid dynamics. In vivo 1H-MRS allows to noninvasively assess hepatic lipid content (HLC) and composition both in humans  and rodents . Transgenic mice provide insight into disease mechanisms but, comparing with bigger subjects, reduced sample size and consequently increased acquisition time to compensate for sensitivity issues, remain limiting factors. We aimed to improve sensitivity and spectral resolution of the 1H-NMR spectrum of the mouse liver employing high magnetic field strength, i.e. 14.1T. Subjects and Methods: Seven C57BL/6J mice (13-20 weeks) under isofluorane anesthesia were scanned in the supine position with a 1H quadrature surface coil over the abdomen. NMR measurements were performed in a horizontal bore 14.1T-26 cm magnet. Multi-slice gradient echo images were acquired in the coronal, sagittal and axial orientations for anatomical identification of the liver. Localized, respiration-gated 1H-NMR spectra were acquired from a 9-15 μl voxel with STEAM (TM, 20 ms; TR, 6.5 s; TE, 8-35 ms; 18-25 scans). Spectra were corrected for B0 drift and phase, summed and analyzed with LCModel. T2 correction was done by mono-exponential fit of peak areas as a function of TE. HLC was estimated as the T2-corrected area of 1.3 ppm-lipid resonance relative to that of the water plus 1.3 ppm-lipid. The quantification method was validated in water-in-oil phantoms (Figure 1). Water suppression was achieved with a Gaussian-shaped pulse during TM period (84 scans). Results: Respiration-gated acquisition yielded well-defined anatomical images of the mouse liver structure (Figure 2) and very stable inter-scans signal intensity (Figure 3). STEAM-determined water T2 was 8.4 ± 0.3 ms, shorter but still comparable with previous reports of ~11 ms with PRESS at 9.4T  and 11.7T . HLC was 1.1 ± 0.1% in young adult mice. Fatty acyl resonances were well resolved in water-suppressed spectra (Figure 4) and choline-containing compounds could be identified. Discussion/Conclusion: We report highly stable localized 1H-MRS of the mouse liver at high field. Enhanced sensitivity allowed for accurate determination of HCL from small voxels confined to hepatic tissue, in short experiment series (~10 min). The saturation profile of the fatty-acyl chains can be determined even for healthy mice with low HLC. This approach opens the possibility to study mice models with very low HLC. References:  Hamilton G, 2011, NMR Biomed 24, 784–790.  Ye Q, 2012, Mang Reson Mater Phy, in press.  Tang H, 2007, Proc Intl Soc Mag Reson Med 15.2012. 29th Annual Scientific Meeting of the European Society for Magnetic Resonace in Medicine and Biology , Lisboa, Portugal , October 4-6, 2012. p. 14-45.
DOI : 10.1007/s10334-012-0321-z.
Hyperpolarized 6Li as probe for hemoglobin oxygenation level2012. ESMRMB 29th Annual Scientific Meeting , Lisbon, Portugal , October 4-6, 2012.
Handling macromolecule signals in the quantification of the neurochemical profile
In vivo localized proton magnetic resonance spectroscopy (1H MRS) became a powerful and unique technique to non-invasively investigate brain metabolism of rodents and humans. The main goal of 1H MRS is the reliable quantification of concentrations of metabolites (neurochemical profile) in a well-defined region of the brain. The availability of very high magnetic field strengths combined with the possibility of acquiring spectra at very short echo time have dramatically increased the number of constituents of the neurochemical profile. The quantification of spectra measured at short echo times is complicated by the presence of macromolecule signals of particular importance at high magnetic fields. An error in the macromolecule estimation can lead to substantial errors in the obtained neurochemical profile. The purpose of the present review is to overview methods of high field 1H MRS with a focus on the metabolite quantification, in particular in handling signals of macromolecules. Three main approaches of handling signals of macromolecules are described, namely mathematical estimation of macromolecules, measurement of macromolecules in vivo, and direct acquisition of the in vivo spectrum without the contribution of macromolecules.
Journal of Alzheimer's disease : JAD
DOI : 10.3233/JAD-2012-120100
Proton and phosphorus magnetic resonance spectroscopy of a mouse model of Alzheimer's disease
The development of new diagnostic criteria for Alzheimer's disease (AD) requires new in vivo markers reflecting early pathological changes in the brain of patients. Magnetic resonance (MR) spectroscopy has been shown to provide useful information about the biochemical changes occurring in AD brain in vivo. The development of numerous transgenic mouse models of AD has facilitated the evaluation of early biomarkers, allowing researchers to perform longitudinal studies starting before the onset of the pathology. In addition, the recent development of high-field animal scanners enables the measurement of brain metabolites that cannot be reliably quantified at lower magnetic fields. In this report, we studied a new transgenic mouse model of AD, the 5xFAD model, by in vivo proton and phosphorus MR spectroscopy. This model, which is characterized by an early-onset and a robust amyloid pathology, developed changes in the neurochemical profile, which are typical in the human disease, i.e., an increase in myo-inositol and a decrease in N-acetylaspartate concentrations, as early as in the 40th week of age. In addition, a significant decrease in the γ-aminobutyrate concentration was observed in transgenic mice at this age compared to controls. The pseudo-first-order rate constant of the creatine kinase reaction as well as relative concentrations of phosphorus-containing metabolites were not changed significantly in the 36 and 72-week old transgenic mice. Overall, these results suggest that mitochondrial activity in the 5 × FAD mice is not substantially affected but that the model is relevant for studying early biomarkers of AD.
Journal of Alzheimer's disease : JAD
DOI : 10.3233/JAD-2012-112072
In vivo detection of brain Krebs cycle intermediate by hyperpolarized magnetic resonance
The Krebs (or tricarboxylic acid (TCA)) cycle has a central role in the regulation of brain energy regulation and metabolism, yet brain TCA cycle intermediates have never been directly detected in vivo. This study reports the first direct in vivo observation of a TCA cycle intermediate in intact brain, namely, 2-oxoglutarate, a key biomolecule connecting metabolism to neuronal activity. Our observation reveals important information about in vivo biochemical processes hitherto considered undetectable. In particular, it provides direct evidence that transport across the inner mitochondria membrane is rate limiting in the brain. The hyperpolarized magnetic resonance protocol designed for this study opens the way to direct and real-time studies of TCA cycle kinetics.Journal of Cerebral Blood Flow & Metabolism advance online publication, 19 September 2012; doi:10.1038/jcbfm.2012.136.
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
DOI : 10.1038/jcbfm.2012.136
A comparison of high-pass birdcage coils for small animal imaging at 9.4 and 14T2012. ESMRMB 29th Annual Scientific Meeting , Lisbon, Portugal , October 4-6, 2012.
The importance of priors for l2 regularization and total variation methods in quantitative susceptibility mapping
Phase imaging has been demonstrated to offer a good contrast between and within brain tissues at 7T with iron and myelin concentration being amongst the main modulators of the observed contrast due to their para- and dia-magnetic properties.Phase imaging suffers from a non-local contrast variation which can be overcome by calculating the underlying magnetic susceptibility maps.As this problem is ill-posed, many regularized methods have been proposed over the past years[2,3,4].The regularized single-orientation (RSO) based on the l2 regularisation and the morphology enabled dipole inversion (MEDI) method based on the l1 total variation incorporate prior knowledge of the expected edges taken from the magnitude image.In this abstract a systematic evaluation is performed of a l2 RSO method[2,5] and a l1 total variation method (TV) using numerical data and different morphology priors.2012. 29th Annual Meeting of the European Society for Magnetic Resonance in Medicine and Biology (ESMRMB) , Lisbon, Portugal , October 4-6, 2012. p. 64.
DOI : 10.1007/s10334-012-0321-z.
Signal enhancement of Glycogen by 13C NMR spectroscopy using broadband 1H decoupling and NOE at 7T2012. 29th Annual scientific meeting of the European Society for Magnetic Resonance in Medicine and Biology (ESMRMB) , Lisbon, Portugal , October 4-6, 2012.
Intra and cross-modal negative BOLD response to contrast-varying visual stimuli
The BOLD contrast is widely used to study brain function. Under externally-applied stimuli, positive BOLD responses (PBR) are generally attributed to local increases in brain activity. Negative BOLD responses (NBR) are also frequently observed, but their underlying neurovascular-coupling mechanisms are less well-understood. Here, we study the NBR to contrast-varying visual stimuli. Both intra-modal (located in regions directly associated with the stimulus) and cross-modal responses (located in functionally-distinct regions) are analyzed.2012. ESMRMB 29th Annual Scientific Meeting , Lisbon, Portugal , October 4-6, 2012.
Localized in vivo hyperpolarization transfer sequences
In vivo localized and fully adiabatic homonuclear and heteronuclear polarization transfer experiments were designed and performed in the rat brain at 9.4 T after infusion of hyperpolarized sodium [1,2-(13) C(2) ] and sodium [1-(13) C] acetate. The method presented herein leads to highly enhanced in vivo detection of short-T(1) (13) C as well as attached protons. This indirect detection scheme allows for probing additional molecular sites in hyperpolarized substrates and their metabolites and can thus lead to improved spectral resolution such as in the case of (13) C-acetate metabolism.
Magnetic Resonance in Medicine
DOI : 10.1002/mrm.23231
Kinetic analysis of acetylCoA synthetase activity in skeletal muscle2012. ESMRMB 29th Annual Scientific Meeting , Lisbon, Portugal , October 4-6, 2012..
In vivo real time cardiac metabolism using hyperpolarized acetate2012. ISMRM , Melbourne , May 2012. p. 4324.
In vivo enzymatic assay of carnitine acetyl transferase and acetylCoA synthetase using hyperpolarized acetate2012. ISMRM , Melbourne , May 2012. p. 4327.
BDPA as a polarizing agent for in vivo hyperpolarized MR experiment2012. Metaflux Meeting , May 2012.
PACEUP-3DEPI: A highly Accelerated 3D-EPI Sequence for fMRI at 7T2012.
Exploring the complementarities of the MP2RAGE and the Sa2RAGE sequences - quantitative T1 mapping2012. Proc. ISMRM 20th Scientific Meeting , Melbourne, Australia .
Phosphorus MRS Study of a Murine Model of Peripheral Arterial Disease2012. ISMRM 20th Annual Scientific Meeting , Melbourne, Australia , 5-11 May 2012.
A high-power RF switch for arterial spin labelling with a separate tagging coil2012. 20th Scientific Meeting of the International Society for Magnetic Resonance in Medicine , Melbourne, Australia , May 5-11, 2012. p. 2685.
A high-pass birdcage coil for small animal imaging at 600MHz/14.1T2012. 20th Scientific Meeting of the International Society for Magnetic Resonance in Medicine , Melbourne, Australia , May 5-11, 2012.
In vivo longitudinal 1H Spectroscopic Imaging and Diffusion Tensor Imaging studies at 9.4T in a rat model of chronic liver failure2012. ISMRM 20th Annual Scientific Meeting , Melbourne, Australia , 5-11 May 2012.
Towards 13C NMR spectroscopy of human muscle at 7T using broadband 1H decoupling2012. 20th Annual meeting of the International Society for Magnetic Resonance in Medicine (ISMRM) , Melbourne, Australia , May 5-11, 2012.
Shared-conductor versus overlapped-loop quadrature surface coils: which performs better in human brain at 7T?2012. 20th Annual Meeting of the International Society for Magnetic Resonance in Medicine , Melbourne, Australia , May 5-11, 2012.
INFLUENCE OF TISSUE SPECIFIC MACROMOLECULE BASELINE ON THE METABOLITE QUANTIFICATION IN HUMAN BRAIN AT 7 TESLA2012. ISMRM 2012 , Melbourne , May 2012.
QUANTIFICATION DIFFERENCES OF 1H SPECTRA IN HUMAN BRAIN AT 3 TESLA USING THE ACQUIRED MACROMOLECULE BASELINE OR THE BUILT-IN LCMODEL SPLINE BASELINE2012. ISMRM 2012 , Melbourne , May 2012.
In vivo Structural Imaging of the Cerebellum, the Contribution of Ultra-High Fields
This review covers some of the contributions to date from cerebellar imaging studies performed at ultra-high magnetic fields. A short overview of the general advantages and drawbacks of the use of such high field systems for imaging is given. One of the biggest advantages of imaging at high magnetic fields is the improved spatial resolution, achievable thanks to the increased available signal-to-noise ratio. This high spatial resolution better matches the dimensions of the cerebellar substructures, allowing a better definition of such structures in the images. The implications of the use of high field systems is discussed for several imaging sequences and image contrast mechanisms. This review covers studies which were performed in vivo in both rodents and humans, with a special focus on studies that were directed towards the observation of the different cerebellar layers.
Cerebellum (London, England)
DOI : 10.1007/s12311-010-0189-2
High temporal resolution and physiological noise removal improve BOLD detection in brainstem and auditory cortex at 7T2012. ISMRM , Melbourne, Australia .
In vivo real-time metabolic studies in mice at physiological concentrations following 1-13C lactate injection
The real-time metabolic transformation of lactate in the mouse head was monitored following the injection of hyperpolarized 1-13C lactate at physiological doses. The results were compared with metabolic studies performed with hyperpolarized 1-13C pyruvate at similar blood concentration. From the observation that the lactate to alanine ratio was nearly identical following both the pyruvate and the lactate injections, we concluded that the substrate and its metabolites can be detected in real time at physiological concentrations after the injection of lactate.ISMRM 20th annual meeting, Merbourne, Australia, May 5 - 11, 2012.
High-field diffusion tensor imaging characterization of cerebral white matter injury in LPS exposed fetal sheep2012.
High‐field diffusion tensor imaging characterization of cerebral white matter injury in LPS exposed fetal sheep2012.
Lactoferrine supplementation following Hypoxia-Ischemia in the immature rat brain: macro-, micro-structural and metabolic assessment of the neuroprotective effect using multimodal MR2012.
A new approach to short-TE full-sensitivity MRSI of human brain at 7T2012. ISMRM 20th Annual Meeting & Exhibition , Melbourne, Australia , May 5-11, 2012.
Proton T1 relaxation times of metabolites in human occipital white matter and grey matter at 7T2012. ISMRM 20th Annual Meeting & Exhibition , Melbourne, Australia , May 5-11, 2012.
Glutamatergic and GABAergic metabolic compartmentation determined by in vivo 13C NMR spectroscopySwiss Society for Neuroscience Annual Meeting, Zürich, February 3, 2012.
N-acetylcysteine normalizes neurochemical changes in the glutathione-deficient schizophrenia mouse model during developmentNCCR SYNAPSY Annual Meeting, Villars, March 30-31, 2012.
Metabolism of [1,6-13C]glucose in glutamatergic and GABAergic compartments in vivo in the rat brain10th International Conference on Brain Energy Metabolism, Monterey, California, April 17-20, 2012.
Brain metabolism in glutamatergic and GABAergic compartments detected by in vivo 13C NMR spectroscopy at 14.1 T2012. ISMRM 20th Scientific Meeting & Exibition . p. 297.
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. Copyright © 2012 by Lippincott Williams & Wilkins.
DOI : 10.1097/RLI.0b013e31824600e9
Measurements of Glycogen Metabolism in the Living Brain
To maintain brain function, the combustion of glucose for the generation of energy (ATP) is essential, yet the brain maintains fuel storage in the form of glial glycogen. Although brain glycogen levels are lower than those in the liver, they exceed the normal free glucose concentration in brain several-fold. Under normoxic conditions, when a partial glucose supply deficit is present, brain glycogen can provide fuel for extended periods of time. Brain glycogen metabolism is active, but comparatively slow, consistent with a role of an emergency fuel with neuroprotective effects. The classical analysis with biochemical means requires tissue extraction; brain glycogen metabolism can be measured directly in the living brain only by 13C NMR spectroscopy. This chapter reviews the insights gained into brain glycogen metabolism in the living brain to-date and reviews potential roles for brain glycogen in the context of neuro-glial metabolism, hypoglycemia and neuroprotection.Neural Metabolism in vivo; Springer,
DOI : 10.1007/978-1-4614-1788-0_22.
Cerebral Glucose Transport and Homeostasis
Cerebral glucose homeostasis is maintained by the equilibrium between glucose transport across the blood-brain-barrier (BBB), which occurs through facilitative carriers, and glucose consumption mainly initiated by hexokinase phosphorylation. Glucose concentrations can be quantified non invasively by nuclear magnetic resonance (NMR) spectroscopy and such measurements, through appropriate mathematical modelling, allow to determine the kinetics of glucose transport and metabolism. This chapter summarizes the insights gained into brain glucose transport from the measurement of the brain glucose concentration, particularly reviewing state of the art NMR methods for non invasive determination of glucose homeostasis and discussing the employment of mathematical models of glucose transport.Neural Metabolism in vivo; Springer,
DOI : 10.1007/978-1-4614-1788-0_20.
Neural metabolism in vivo
Neural Metabolism In Vivo strives to offer a comprehensive and fundamental overview of cerebral metabolism by presenting leading-edge in vivo multimodal technology and its application in assessing neural activity, energy metabolism and neurotransmission in the living brain. The recent advances in our current understanding of the complex and dynamic physiological and neurochemical processes of neural function and metabolism are indebted to a variety of powerful techniques, namely nuclear magnetic resonance, positron emission tomography, radiotracer imaging, optical imaging and micro-dialysis. With the advent of these in vivo techniques, the collective and devoted efforts of neuroscientists and bioengineers made the brain readily assessable to demystify its complexity. Specific topics of this volume include energy metabolism specific to the brain from the in vivo assessment of neural activity via neurovascular coupling and glucose uptake, as well as the accompanying consumption of various cerebral energy substrates to metabolic compartmentation and interaction between neurons and astrocytes. This exciting compilation of 41 chapters across two volumes is the result of the dedicated efforts of 99 renowned experts in neurobiology.Springer.
Continuous arterial spin labeling of mouse cerebral blood flow using an actively-detuned two-coil system at 9.4T
Among numerous magnetic resonance imaging (MRI) techniques, perfusion MRI provides insight into the passage of blood through the brain's vascular network non-invasively. Studying disease models and transgenic mice would intrinsically help understanding the underlying brain functions, cerebrovascular disease and brain disorders. This study evaluates the feasibility of performing continuous arterial spin labeling (CASL) on all cranial arteries for mapping murine cerebral blood flow at 9.4 T. We showed that with an active-detuned two-coil system, a labeling efficiency of 0.82 ± 0.03 was achieved with minimal magnetization transfer residuals in brain. The resulting cerebral blood flow of healthy mouse was 99 ± 26 mL/100g/min, in excellent agreement with other techniques. In conclusion, high magnetic fields deliver high sensitivity and allowing not only CASL but also other MR techniques, i.e. (1)H MRS and diffusion MRI etc, in studying murine brains.2012. 33rd Annual International Conference of the IEEE Engineering-in-Medicine-and-Biology-Society (EMBS) , Boston, MA , Aug 30-Sep 03, 2011. p. 6993-6.
DOI : 10.1109/IEMBS.2011.6091768.
The neurochemical profile quantified by in vivo(1)H NMR spectroscopy
Proton NMR spectroscopy is emerging from translational and preclinical neuroscience research as an important tool for evidence based diagnosis and therapy monitoring. It provides biomarkers that offer fingerprints of neurological disorders even in cases where a lesion is not yet observed in MR images. The collection of molecules used as cerebral biomarkers that are detectable by (1)H NMR spectroscopy define the so-called "neurochemical profile". The non-invasive quality of this technique makes it suitable not only for diagnostic purposes but also for therapy monitoring paralleling an eventual neuroprotection. The application of (1)H NMR spectroscopy in basic and translational neuroscience research is discussed here.
DOI : 10.1016/j.neuroimage.2011.12.038
A comparison of in vivo (13) C MR brain glycogen quantification at 9.4 and 14.1 T
The high molecular weight and low concentration of brain glycogen render its noninvasive quantification challenging. Therefore, the precision increase of the quantification by localized (13) C MR at 9.4 to 14.1 T was investigated. Signal-to-noise ratio increased by 66%, slightly offset by a T(1) increase of 332 ± 15 to 521 ± 34 ms. Isotopic enrichment after long-term (13) C administration was comparable (∼40%) as was the nominal linewidth of glycogen C1 (∼50 Hz). Among the factors that contributed to the 66% observed increase in signal-to-noise ratio, the T(1) relaxation time impacted the effective signal-to-noise ratio by only 10% at a repetition time = 1 s. The signal-to-noise ratio increase together with the larger spectral dispersion at 14.1 T resulted in a better defined baseline, which allowed for more accurate fitting. Quantified glycogen concentrations were 5.8 ± 0.9 mM at 9.4 T and 6.0 ± 0.4 mM at 14.1 T; the decreased standard deviation demonstrates the compounded effect of increased magnetization and improved baseline on the precision of glycogen quantification. Magn Reson Med, 2011. © 2011 Wiley Periodicals, Inc.
DOI : 10.1002/mrm.23192
SA2RAGE: A new sequence for fast B(1) ( ) -mapping
At high magnetic field strengths (≥3T), the radiofrequency wavelength used in MRI is of the same order of magnitude of (or smaller than) the typical sample size, making transmit magnetic field (B 1 ) inhomogeneities more prominent. Methods such as radiofrequency-shimming and transmit SENSE have been proposed to mitigate these undesirable effects. A prerequisite for such approaches is an accurate and rapid characterization of the B 1 field in the organ of interest. In this work, a new phase-sensitive three-dimensional B 1 -mapping technique is introduced that allows the acquisition of a 64 × 64 × 8 B 1 -map in ∼20 s, yielding an accurate mapping of the relative B 1 with a 10-fold dynamic range (0.2-2 times the nominal B 1 ). Moreover, the predominant use of low flip angle excitations in the presented sequence minimizes specific absorption rate, which is an important asset for in vivo B 1 -shimming procedures at high magnetic fields. The proposed methodology was validated in phantom experiments and demonstrated good results in phantom and human B 1 -shimming using an 8-channel transmit-receive array. Magn Reson Med, 2011. © 2011 Wiley-Liss, Inc.
DOI : 10.1002/mrm.23145
N-acetylcysteine normalizes neurochemical changes in the glutathione-deficient schizophrenia mouse model during development
Background: Glutathione (GSH) is the major cellular redox-regulator and antioxidant. Redox-imbalance due to genetically impaired GSH synthesis is among the risk factors for schizophrenia. Here we used a mouse model with chronic GSH deficit induced by knockout (KO) of the key GSH-synthesizing enzyme, glutamate-cysteine ligase modulatory subunit (GCLM). Methods: With high-resolution magnetic resonance spectroscopy at 14.1 T, we determined the neurochemical profile of GCLM-KO, heterozygous, and wild-type mice in anterior cortex throughout development in a longitudinal study design. Results: Chronic GSH deficit was accompanied by an elevation of glutamine (Gln), glutamate (Glu), Gln/Glu, N-acetylaspartate, myo-Inositol, lactate, and alanine. Changes were predominantly present at prepubertal ages (postnatal days 20 and 30). Treatment with N-acetylcysteine from gestation on normalized most neurochemical alterations to wild-type level. Conclusions: Changes observed in GCLM-KO anterior cortex, notably the increase in Gln, Glu, and Gln/Glu, were similar to those reported in early schizophrenia, emphasizing the link between redox imbalance and the disease and validating the model. The data also highlight the prepubertal period as a sensitive time for redox-related neurochemical changes and demonstrate beneficial effects of early N-acetylcysteine treatment. Moreover, the data demonstrate the translational value of magnetic resonance spectroscopy to study brain disease in preclinical models. © 2012 Society of Biological Psychiatry.
DOI : 10.1016/j.biopsych.2011.07.035
Assessment Of Cerebral Osmotic Regulation In A Rat Model Of Biliary Cirrhosis Using MR Spectroscopy2012. 47th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL) , Barcelona, SPAIN , Apr 18-22, 2012. p. S231-S232.
MRS Frontal Glutathione Levels Correlate with DSI White Matter Integrity Measure in Control Subjects but Not in Early Psychosis Patients2012. 67th Annual Scientific Convention and Meeting of the Society-of-Biological-Psychiatry , Philadelphia, PA , May 03-05, 2012. p. 259S-259S.
Investigation of Network Metrics Correlation with Frontal Glutathione Levels in Control and First Episode Psychosis Subjects2012. 67th Annual Scientific Convention and Meeting of the Society-of-Biological-Psychiatry , Philadelphia, PA , May 03-05, 2012. p. 254S-254S.
Characterization of cerebral glucose dynamics in vivo with a four-state conformational model of transport at the blood-brain barrier
Determination of brain glucose transport kinetics in vivo at steady-state typically does not allow distinguishing apparent maximum transport rate (Tmax) from cerebral consumption rate. Using a four-state conformational model of glucose transport, we show that simultaneous dynamic measurement of brain and plasma glucose concentrations provide enough information for independent and reliable determination of the two rates. In addition, although dynamic glucose homeostasis can be described with a reversible MichaelisMenten model, which is implicit to the large iso-inhibition constant (Kii) relative to physiological brain glucose content, we found that the apparent affinity constant (Kt) was better determined with the four-state conformational model of glucose transport than with any of the other models tested. Furthermore, we confirmed the utility of the present method to determine glucose transport and consumption by analysing the modulation of both glucose transport and consumption by anaesthesia conditions that modify cerebral activity. In particular, deep thiopental anaesthesia caused a significant reduction of both Tmax and cerebral metabolic rate for glucose consumption. In conclusion, dynamic measurement of brain glucose in vivo in function of plasma glucose allows robust determination of both glucose uptake and consumption kinetics.
Journal Of Neurochemistry
DOI : 10.1111/j.1471-4159.2012.07688.x
Cerebral glutamine metabolism under hyperammonemia determined in vivo by localized H-1 and N-15 NMR spectroscopy
Brain glutamine synthetase (GS) is an integral part of the glutamate-glutamine cycle and occurs in the glial compartment. In vivo Magnetic Resonance Spectroscopy (MRS) allows noninvasive measurements of the concentrations and synthesis rates of metabolites. N-15 MRS is an alternative approach to C-13 MRS. Incorporation of labeled N-15 from ammonia in cerebral glutamine allows to measure several metabolic reactions related to nitrogen metabolism, including the glutamate-glutamine cycle. To measure N-15 incorporation into the position 5N of glutamine and position 2N of glutamate and glutamine, we developed a novel N-15 pulse sequence to simultaneously detect, for the first time, [5-N-15] Gln and [2-N-15]Gln Glu in vivo in the rat brain. In addition, we also measured for the first time in the same experiment localized H-1 spectra for a direct measurement of the net glutamine accumulation. Mathematical modeling of H-1 and N-15 MRS data allowed to reduce the number of assumptions and provided reliable determination of GS (0.30 /- 0.050 mu mol/g per minute), apparent neurotransmission (0.26 /- 0.030 mu mol/g per minute), glutamate dehydrogenase (0.029 /- 0.002 mu mol/g per minute), and net glutamine accumulation (0.033 /- 0.001 mu mol/g per minute). These results showed an increase of GS and net glutamine accumulation under hyperammonemia, supporting the concept of their implication in cerebral ammonia detoxification. Journal of Cerebral Blood Flow & Metabolism (2012) 32, 696-708; doi:10.1038/jcbfm.2011.173; published online 14 December 2011
Journal Of Cerebral Blood Flow And Metabolism
DOI : 10.1038/jcbfm.2011.173
In vivo metabolic profiling of glioma-initiating cells using proton magnetic resonance spectroscopy at 14.1 Tesla
In the last decade, evidence has emerged indicating that the growth of a vast majority of tumors including gliomas is sustained by a subpopulation of cancer cells with stem cell properties called cancer initiating cells. These cells are able to initiate and propagate tumors and constitute only a fraction of all tumor cells. In the present study, we showed that intracerebral injection of cultured glioma-initiating cells into nude mice produced fast growing tumors showing necrosis and gadolinium enhancement in MR images, whereas gliomas produced by injecting freshly purified glioma-initiating cells grew slowly and showed no necrosis and very little gadolinium enhancement. Using proton localized spectroscopy at 14.1 Tesla, decreasing trends of N-acetylaspartate, glutamate and glucose concentrations and an increasing trend of glycine concentration were observed near the injection site after injecting cultured glioma-initiating cells. In contrast to the spectra of tumors grown from fresh cells, those from cultured cells showed intense peaks of lipids, increased absolute concentrations of glycine and choline-containing compounds, and decreased concentrations of glutamine, taurine and total creatine, when compared with a contralateral non-tumor-bearing brain tissue. A decrease in concentrations of N-acetylaspartate and -aminobutyrate was found in both tumor phenotypes after solid tumor formation. Further investigation is needed to determine the cause of the dissimilarities between the tumors grown from cultured glioma-initiating cells and those from freshly purified glioma-initiating cells, both derived from human glioblastomas. Copyright (C) 2011 John Wiley & Sons, Ltd.
Nmr In Biomedicine
DOI : 10.1002/nbm.1763
High-resolution spatial mapping of changes in the neurochemical profile after focal ischemia in mice
After ischemic stroke, the ischemic damage to brain tissue evolves over time and with an uneven spatial distribution. Early irreversible changes occur in the ischemic core, whereas, in the penumbra, which receives more collateral blood flow, the damage is more mild and delayed. A better characterization of the penumbra, irreversibly damaged and healthy tissues is needed to understand the mechanisms involved in tissue death. MRSI is a powerful tool for this task if the scan time can be decreased whilst maintaining high sensitivity. Therefore, we made improvements to a H-1 MRSI protocol to study middle cerebral artery occlusion in mice. The spatial distribution of changes in the neurochemical profile was investigated, with an effective spatial resolution of 1.4 mu L, applying the protocol on a 14.1-T magnet. The acquired maps included the difficult-to-separate glutamate and glutamine resonances and, to our knowledge, the first mapping of metabolites gamma-aminobutyric acid and glutathione in vivo, within a metabolite measurement time of 45min. The maps were in excellent agreement with findings from single-voxel spectroscopy and offer spatial information at a scan time acceptable for most animal models. The metabolites measured differed with respect to the temporal evolution of their concentrations and the localization of these changes. Specifically, lactate and N-acetylaspartate concentration changes largely overlapped with the T-2-hyperintense region visualized with MRI, whereas changes in cholines and glutathione affected the entire middle cerebral artery territory. Glutamine maps showed elevated levels in the ischemic striatum until 8h after reperfusion, and until 24h in cortical tissue, indicating differences in excitotoxic effects and secondary energy failure in these tissue types. Copyright (C) 2011 John Wiley & Sons, Ltd.
Nmr In Biomedicine
DOI : 10.1002/nbm.1740
A two-compartment mathematical model of neuroglial metabolism using [1-C-11] acetate
The purpose of this study was to develop a two-compartment metabolic model of brain metabolism to assess oxidative metabolism from [1-C-11] acetate radiotracer experiments, using an approach previously applied in C-13 magnetic resonance spectroscopy (MRS), and compared with an one-tissue compartment model previously used in brain [1-C-11] acetate studies. Compared with C-13 MRS studies, C-11 radiotracer measurements provide a single uptake curve representing the sum of all labeled metabolites, without chemical differentiation, but with higher temporal resolution. The reliability of the adjusted metabolic fluxes was analyzed with Monte-Carlo simulations using synthetic C-11 uptake curves, based on a typical arterial input function and previously published values of the neuroglial fluxes V-tca(g), V-x, V-nt, and V-tca(n) measured in dynamic C-13 MRS experiments. Assuming V-x(g)=10xV(tca)(g) and V-x(n)=V-tca(n), it was possible to assess the composite glial tricarboxylic acid (TCA) cycle flux V-gt(g) (Vgtg = V(x)(g)xV(tca)(g)/(V-x(g) V-tca(g))) and the neurotransmission flux V-nt from C-11 tissue-activity curves obtained within 30 minutes in the rat cortex with a beta-probe after a bolus infusion of [1-C-11] acetate (n = 9), resulting in V-gt(g) = 0.136 /- 0.042 and V-nt = 0.170 /- 0.103 mu mol/g per minute (mean /- s.d. of the group), in good agreement with 13C MRS measurements. Journal of Cerebral Blood Flow & Metabolism (2012) 32, 548-559; doi: 10.1038/jcbfm.2011.162; published online 30 November 2011
Journal Of Cerebral Blood Flow And Metabolism
DOI : 10.1038/jcbfm.2011.162
Temporal SNR characteristics in segmented 3D-EPI at 7T
Three-dimensional segmented echo planar imaging (3D-EPI) is a promising approach for high-resolution functional magnetic resonance imaging, as it provides an increased signal-to-noise ratio (SNR) at similar temporal resolution to traditional multislice 2D-EPI readouts. Recently, the 3D-EPI technique has become more frequently used and it is important to better understand its implications for fMRI. In this study, the temporal SNR characteristics of 3D-EPI with varying numbers of segments are studied. It is shown that, in humans, the temporal variance increases with the number of segments used to form the EPI acquisition and that for segmented acquisitions, the maximum available temporal SNR is reduced compared to single shot acquisitions. This reduction with increased segmentation is not found in phantom data and thus likely due to physiological processes. When operating in the thermal noise dominated regime, fMRI experiments with a motor task revealed that the 3D variant outperforms the 2D-EPI in terms of temporal SNR and sensitivity to detect activated brain regions. Thus, the theoretical SNR advantage of a segmented 3D-EPI sequence for fMRI only exists in a low SNR situation. However, other advantages of 3D-EPI, such as the application of parallel imaging techniques in two dimensions and the low specific absorption rate requirements, may encourage the use of the 3D-EPI sequence for fMRI in situations with higher SNR. Magn Reson Med, 2012. (C) 2011 Wiley Periodicals, Inc.
Magnetic Resonance In Medicine
DOI : 10.1002/mrm.23007
In vivo assessment of myelination by phase imaging at high magnetic field
The present study evaluated the potential of using the phase of T-2* weighted MR images to characterize myelination during brain development and pathology in rodents at 9.4 T. Phase contrast correlated with myelin content assessed by histology and suggests that most contrast between white and cortical gray matter is modulated by myelin. Ex vivo experiments showed that gray-white matter phase contrast remains unchanged after iron extraction. In dysmyelinated shiverer mice, phase imaging correlated strongly with myelin staining, showing reduced contrast between white and gray matter when compared to healthy controls. We conclude that high-resolution phase images, acquired at high field, allow assessment of myelination and dysmyelination. (C) 2011 Elsevier Inc. All rights reserved.
DOI : 10.1016/j.neuroimage.2011.09.057
Prospective and retrospective motion correction in diffusion magnetic resonance imaging of the human brain
Diffusion-weighting in magnetic resonance imaging (MRI) increases the sensitivity to molecular Brownian motion, providing insight in the micro-environment of the underlying tissue types and structures. At the same time, the diffusion weighting renders the scans sensitive to other motion, including bulk patient motion. Typically, several image volumes are needed to extract diffusion information, inducing also inter-volume motion susceptibility. Bulk motion is more likely during long acquisitions, as they appear in diffusion tensor, diffusion spectrum and q-ball imaging. Image registration methods are successfully used to correct for bulk motion in other MRI time series, but their performance in diffusion-weighted MRI is limited since diffusion weighting introduces strong signal and contrast changes between serial image volumes.
DOI : 10.1016/j.neuroimage.2011.07.004
Spread spectrum magnetic resonance imaging
We propose a novel compressed sensing technique to accelerate the magnetic resonance imaging (MRI) acquisition process. The method, coined spread spectrum MRI or simply s2MRI, consists of pre-modulating the signal of interest by a linear chirp before random k-space under-sampling, and then reconstructing the signal with non-linear algorithms that promote sparsity. The effectiveness of the procedure is theoretically underpinned by the optimization of the coherence between the sparsity and sensing bases. The proposed technique is thoroughly studied by means of numerical simulations, as well as phantom and in vivo experiments on a 7T scanner. Our results suggest that s2MRI performs better than state-of-the-art variable density k-space under-sampling approaches. Code: http://lts2www.epfl.ch/people/gilles/softwares
IEEE Transactions on Medical Imaging
DOI : 10.1109/TMI.2011.2173698
GLIAL GLYCOLYTIC GAPDH ACTIVITY MODULATES THE RESTING CEREBRAL METABOLIC RATE OF GLUCOSE AND CA 2- DEPENDENT EXCITATORY NEUROTRANSMITTER RELEASE2011. Brain 2011 , Barcelona, Spain , 25-28 May, 2011. p. 133.
OXIDATIVE STRESS AND SCHIZOPHRENIA: 1H-MRS AT 14.1 T IN DEVELOPING MICE WITH GLUTATHIONE DEFICIT2011. 13th International Congress on Schizophrenia Research (ICSR) , Colorado Springs, CO , Apr 02-06, 2011. p. 123-123.
Abrogation of glutamate consumption in the central nervous system modifies brain metabolism and reshapes peripheral energy distribution2011. p. S62-S62.
Magnetic resonance imaging (MRI) of high resolution quantitative detection of pancreatic islets in pancreas individual integers2011. p. A6-A6.
Preparation with fasting and acipimox increases myocardial glucose uptake in mice during cardiac 18F-FDG microPET2011. p. A108-A109.
In vivo metabolic profiling of glioma-initiating cells using proton magnetic resonance spectroscopy at 14.1 Tesla2011. p. S15-S15.
Localized in vivo hyperpolarization transfer experiments2011. 19th Annual ISMRM Meeting , Montreal, Canada , May 7-13, 2011. p. 3530.
In vivo detection of brain Krebs cycle intermediate by hyperpolarized MR2011. 19th Annual ISMRM Meeting , Montreal, Canada , May 7-13, 2011.. p. 660.
In vivo real-time metabolic studies of mice brain and skeletal muscle at 9.4T2011. Third International Symposium on Dynamic Nuclear Polarization , Lausanne , September 2011.
The metabolic effect of hyperpolarized [1-13C]acetate dosage in vivo2011. Third International Symposium on Dynamic Nuclear Polarization , Lausanne , September 2011.
Kinetics of hyperpolarized [1-13C]acetate metabolism in cardiac muscle2011. Third International Symposium on Dynamic Nuclear Polarization , Lausanne , September 2011.
Study of acetylcarnitine kinetics in skeletal muscle in vivo using hyperpolarized 1-13C acetate2011. ISMRM , Montreal , May 2011. p. 3536.
Hyperpolarized acetate as a metabolic tracer for skeletal and cardiac muscle energetics2011. Hot Topics in Molecular Imaging - TOPIM , Les Houches , January 2011.
Mapping inversion efficiencies of adiabatic pulses at 7T2011.
Continuous Arterial Spin Labeling of Mouse Cerebral Blood Flow Using an Actively-Detuned Two-Coil System at 9.4T
Among numerous magnetic resonance imaging (MRI) techniques, perfusion MRI provides insight into the passage of blood through the brain's vascular network non-invasively. Studying disease models and transgenic mice would intrinsically help understanding the underlying brain functions, cerebrovascular disease and brain disorders. This study evaluates the feasibility of performing continuous arterial spin labeling (CASL) on all cranial arteries for mapping murine cerebral blood flow at 9.4T. We showed that with an active-detuned two-coil system, a labeling efficiency of 0.82 /- 0.03 was achieved with minimal magnetization transfer residuals in brain. The resulting cerebral blood flow of healthy mouse was 99 /- 26mL/100g/min, in excellent agreement with other techniques. In conclusion, high magnetic fields deliver high sensitivity and allowing not only CASL but also other MR techniques, i.e. H-1 MRS and diffusion MRI etc, in studying murine brains.2011. 33rd Annual International Conference of the IEEE Engineering-in-Medicine-and-Biology-Society (EMBS) , Boston, MA , Aug 30-Sep 03, 2011. p. 6993-6996.
Proton and phosphorus MRS of a 5xFAD mouse model of Alzheimer's disease2011. ISMRM 19th Annual Meeting & Exhibition , Montreal, Canada , May 7-13, 2011.
High-resolution mapping of the neurochemical profile after focal ischemia in mice2011. ISMRM 19th Annual Meeting & Exhibition , Montreal, Canada , May 7-13, 2011.
High-resolution spatial mapping of changes in the neurochemical profile after focal ischemia in mice2011. 19th Scientific Meeting of the International Society for Magnetic Resonance in Medicine , Montréal, Québec, Canada , 7-13 May 2011.
Continuous Arterial Spin Labeling (CASL) of Cerebral Blood Flow of Mouse at 9.4T2011. 19th Scientific Meeting of the International Society for Magnetic Resonance in Medicine, 2011 , Montréal, Québec, Canada , 7-13 May 2011.
Early metabolic changes in the amyotrophic lateral sclerosis SOD1 mouse brain are revealed using 1H MRS rather than CASL and 18FDG PET2011. 19th Scientific Meeting of the International Society for Magnetic Resonance in Medicine, 2011 , Montréal, Québec, Canada .
Early metabolic biomarkers identifying permanent stroke in mouse brain using 1H MRS2011. 19th Scientific Meeting of the International Society for Magnetic Resonance in Medicine , Montréal, Québec, Canada , 7-13 May 2011.
In vivo longitudinal 1H MRS study of transgenic mouse models of prion disease in the hippocampus and cerebellum at 14.1T2011. ISMRM 19th Annual Scientific Meeting , Montreal, Canada , 7-13 May 2011.
In vivo localized 15N MRS detection of hyperpolarized 15N labeled choline in the rat brain2011. ISMRM 19th Annual Scientific Meeting , Montreal, Canada , 7-13 May 2011.
Impact of the prior knowledge on the quantification of in vivo 13C spectra using two different algorithms: LCModel and AMARES2011. ISMRM 19th Annual Scientific Meeting , Montreal, Canada , 7-13 May 2011.
Imaging the in vivo effect of hyperammonemia in the rat brain: a Spectroscopic Imaging and Diffusion Tensor Imaging study2011. BRAIN’11 & BRAINPET’11 , Barcelona, Spain , 24-28 May 2011.
Short Erythropoietin treatment following Hypoxia-Ischemia in the immature rat brain: macro-, micro-structural and metabolic assessment using multimodal MR2011.
Hindered or restricted predominance of the diffusion weighted signal function of the diffusion time at ultra-high magnetic field.2011.
Evaluation of glial metabolic fluxes in vivo with [2-13C] acetate infusion in mouse brain by 1H-[13C] NMR spectroscopy2011. ESMRMB CONGRESS 2011 28th Annual Scientific Meeting , Leipzig,Germany , October 6-8, 2011.
In vivo 1H MRS study of a mouse model for fragile-X-associated tremor/ataxia syndrome at 14.1 T2011. ESMRMB CONGRESS 2011 28th Annual Scientific Meeting , Leipzig, Germany , October 6-8, 2011.
In Vivo Assessment of Neuronal Metabolic Fluxes in Mouse Brain by 1H-[13C] NMR Spectroscopy2011. ISMRM 19th Annual Meeting & Exhibition , Montréal, Québec, Canada , May 7-13, 2011.
Cerebral metabolic compartmentation determined by high resolution in vivo 13C NMR spectroscopySwiss Society for Neuroscience Annual Meeting 2011, Basel, Switzerland, March 26, 2011.
Brain metabolism by in vivo 13C NMR spectroscopy25th International Symposium on Cerebral Blood Flow, Metabolism and Function & 10th International Conference on Quantification of Brain Function with PET, Barcelona, Spain, May 25-28, 2011..
Second order proton traps for multi-nuclear RF coils: Applied for 13C MRS in humans at 7T
The concept of second order proton traps (consisting of an inductor and two capacitors) in coils for non-proton NMR allows control over the resonance frequency, the blocking frequency and the trap mode frequency. Effective proton traps with relatively high LTr, and thus very effective blocking, can be constructed, which impose only small degradation of the non-1H coil sensitivity.2011. 28th Annual Scientific Meeting of the European Society for Magnetic Resonance in Medicine and Biology , Leipzig, Germany , October 6-8, 2011. p. 240.
Dynamics of cerebral glucose analysed in vivo with a four-state conformational model2011. ISMRM 19th Scientific Meeting & Exibition . p. 4175.
In vivo 13C NMR spectroscopy at 14.1 T2011. ISMRM 19th Scientific Meeting & Exibition . p. 4172.
Cortical metabolic alterations induced by genetic redox deregulation in GCLM KO mice and the protective effect of N-acetylcysteine treatment – Relevance for schizophrenia2011. ISMRM 19th Scientific Meeting & Exibition . p. 4191.
Neurochemical profile in the hippocampus of aging mice as detected by in vivo 1H NMR spectroscopy at 14.1 T2011. ISMRM 19th Scientific Meeting & Exibition . p. 4171.
Phosphocreatine line with changes in localised 31P MRS of exercising muscle at 7T
The aim was to investigate changes in the line width of high-energy phosphates solely originating from the intramyocellular compartment by temporally resolved localised 31P-MRS after aerobic calf muscle exercise. Semi-Laser  localised 31P-MRS of gastrocnemius muscle and pulse-acquire-MRS (10cm-surface coil) were performed alternatingley in three exercise bouts separated by >20min inactivity. PCr and Pi were quantified in AMARES from single acquitsitions, with TR=6s. While Pi line width is known to change due to pH, to our knowledge this is the first observation of an exercise induced line width increase of intra-myocellular PCr, which may be associated with myoglobin deoxygenation.2011. 28th Annual Scientific Meeting of the European Society for Magnetic Resonance in Medicine and Biology , Leipzig, Germany , October 6-8, 2011. p. 642.
Proton traps for multi-nuclear RF coils: design analysis and practical implementation for 13C MRS in humans at 7T
Trapped coil designs allow the operation of lower-frequency coils in the presence of a proton coil. Adding a second capacitor to a trap in the non-proton RF coil allows control over the trap reactance at the low and high frequency (here 13C and 1H) and the frequency of the trap mode. We demonstrate the interdependence of the parameters controlled and show analytical and numerical solutions to fulfill the design constraints. Our experiments show that, using the simulations, it possible to construct an effective second order trap for 13C at 7T.2011. 19th Annual Meeting ISMRM , Montréal, Canada , 2011. p. #1889.
Nested Surface Coils for Multinuclear NMR
This article introduces the design of surface coils for multinuclear applications. The relative sensitivities of several NMR-visible nuclei of biological interest are considered, and the motivations to operate an RF coil at multiple frequencies, both sequentially and simultaneously, are reviewed. The design of nested surface coils is then developed. Magnetic fields generated by planar loop and butterfly coils are first introduced. The benefits of quadrature design are briefly considered, and methods for combining coils to produce a quadrature field are investigated. These designs are then extended to dual-nuclei coils using multiple, geometrically decoupled loops. The insertion of trap circuits into the low-frequency coil, as an alternative to geometric decoupling, is then considered. Finally, the optimum placement of filters is discussed to prevent noise injection from the RF power amplifiers and to prevent the preamplifiers from saturating during J-decoupling.Encyclopedia of Magnetic Resonance; Chichester: John Wiley & Sons,
DOI : 10.1002/9780470034590.emrstm1192.
Effect of manganese chloride on the neurochemical profile of the rat hypothalamus
Manganese (Mn 2 )-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 Mn 2 -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 Mn 2 produces alterations of the hypothalamic physiological processes are not well understood. 1 H-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 Mn 2 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 Mn 2 exposure. An increase in glutamine levels could also be a characteristic response of the hypothalamus to DIA. © 2011 ISCBFM All rights reserved.
Journal of Cerebral Blood Flow and Metabolism
DOI : 10.1038/jcbfm.2011.92
Detection of neuronal activity and metabolism in a model of dehydration-induced anorexia in rats at 14.1T 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 14.1T. 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 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. © 2011 John Wiley & Sons, Ltd.
NMR in Biomedicine
DOI : 10.1002/nbm.1694
Compartmentalized Cerebral Metabolism of [1,6-(13)C]Glucose Determined by in vivo (13)C NMR Spectroscopy at 14.1 T
Cerebral metabolism is compartmentalized between neurons and glia. Although glial glycolysis is thought to largely sustain the energetic requirements of neurotransmission while oxidative metabolism takes place mainly in neurons, this hypothesis is matter of debate. The compartmentalization of cerebral metabolic fluxes can be determined by (13)C nuclear magnetic resonance (NMR) spectroscopy upon infusion of (13)C-enriched compounds, especially glucose. Rats under light α-chloralose anesthesia were infused with [1,6-(13)C]glucose and (13)C enrichment in the brain metabolites was measured by (13)C NMR spectroscopy with high sensitivity and spectral resolution at 14.1 T. This allowed determining (13)C enrichment curves of amino acid carbons with high reproducibility and to reliably estimate cerebral metabolic fluxes (mean error of 8%). We further found that TCA cycle intermediates are not required for flux determination in mathematical models of brain metabolism. Neuronal tricarboxylic acid cycle rate (V(TCA)) and neurotransmission rate (V(NT)) were 0.45 ± 0.01 and 0.11 ± 0.01 μmol/g/min, respectively. Glial V(TCA) was found to be 38 ± 3% of total cerebral oxidative metabolism, accounting for more than half of neuronal oxidative metabolism. Furthermore, glial anaplerotic pyruvate carboxylation rate (V(PC)) was 0.069 ± 0.004 μmol/g/min, i.e., 25 ± 1% of the glial TCA cycle rate. These results support a role of glial cells as active partners of neurons during synaptic transmission beyond glycolytic metabolism.
Frontiers in neuroenergetics
DOI : 10.3389/fnene.2011.00003
Development of a BOLD fMRI protocol to investigate the mouse barrel cortex at high field2011
Developmental and metabolic brain alterations in rats exposed to bisphenol A during gestation and lactation
In recent years, considerable research has focused on the biological effect of endocrine-disrupting chemicals. Bisphenol A (BPA) has been implicated as an endocrine-disrupting chemical (EDC) due to its ability to mimic the action of endogenous estrogenic hormones.
International Journal Of Developmental Neuroscience
DOI : 10.1016/j.ijdevneu.2010.09.009
Longitudinal MR Assessment of Hypoxic Ischemic Injury in the Immature Rat Brain
Extremely preterm infants commonly show brain injury with long-term structural and functional consequences. Three-day-old (P3) rat pups share some similarities in terms of cerebral development with the very preterm infant (born at 24-28 weeks of gestation). The aim of this study was to assess longitudinally the cerebral structural and metabolic changes resulting from a moderate neonatal hypoxic ischemic injury in the P3 rat pup using high-field (9.4 T) MRI and localized H-1 magnetic resonance spectroscopy techniques. The rats were scanned longitudinally at P3, P4, P11, and P25. Volumetric measurements showed that the percentage of cortical loss in the long term correlated with size of damage 6 h after hypoxia-ischemia, male pups being more affected than female. The neurochemical profiles revealed an acute decrease of most of metabolite concentrations and an increase in lactate 24 h after hypoxia-ischemia, followed by a recovery phase leading to minor metabolic changes at P25 in spite of an abnormal brain development. Further, the increase of lactate concentration at P4 correlated with the cortical loss at P25, giving insight into the early prediction of long-term cerebral alterations following a moderate hypoxia-ischemia insult that could be of interest in clinical practice. Magn Reson Med 65:305-312, 2011. (C) 2010 Wiley-Liss, Inc.
Magnetic Resonance In Medicine
DOI : 10.1002/mrm.22617
Diffusion Tensor Echo Planar Imaging Using Surface Coil Transceiver with a Semiadiabatic RF Pulse Sequence at 14.1T
Diffusion magnetic resonance studies of the brain are typically performed using volume coils. Although in human brain this leads to a near optimal filling factor, studies of rodent brain must contend with the fact that only a fraction of the head volume can be ascribed to the brain. The use of surface coil as transceiver increases Signal-to-Noise Ratio (SNR), reduces radiofrequency power requirements and opens the possibility of parallel transmit schemes, likely to allow efficient acquisition schemes, of critical importance for reducing the long scan times implicated in diffusion tensor imaging. This study demonstrates the implementation of a semiadiabatic echo planar imaging sequence (echo time = 40 ms, four interleaves) at 14.1T using a quadrature surface coil as transceiver. It resulted in artifact free images with excellent SNR throughout the brain. Diffusion tensor derived parameters obtained within the rat brain were in excellent agreement with reported values. Magn Reson Med 65:732-737, 2011. (C) 2010 Wiley-Liss, Inc.
Magnetic Resonance In Medicine
DOI : 10.1002/mrm.22656
Increase of [F-18]FLT Tumor Uptake In Vivo Mediated by FdUrd: Toward Improving Cell Proliferation Positron Emission Tomography
3'-deoxy-3'-[F-18]fluorothymidine ([F-18]FLT), a cell proliferation positron emission tomography (PET) tracer, has been shown in numerous tumors to be more specific than 2-deoxy-2-[F-18]fluoro-d-glucose ([F-18]FDG) but less sensitive. We studied the capacity of a nontoxic concentration of 5-fluoro-2'-deoxyuridine (FdUrd), a thymidine synthesis inhibitor, to increase uptake of [F-18]FLT in tumor xenografts.
Molecular Imaging And Biology
DOI : 10.1007/s11307-010-0368-z
Head Motion Detection Using FID Navigators
This work explores a concept for motion detection in brain MR examinations using high channel-count RF coil arrays. It applies ultrashort (< 100 mu sec) free induction decay signals, making use of the knowledge that motion induces variations in these signals when compared to a reference free induction decay signal. As a proof-of-concept, the method was implemented in a standard structural MRI sequence. The stability of the free induction decay-signal was verified in phantom experiments. Human experiments demonstrated that the observed variations in the navigator data provide a sensitive measure for detection of relevant and common subject motion patterns. The proposed methodology provides a means to monitor subject motion throughout a MRI scan while causing little or no impact on the sequence timing and image contrast. It could hence complement available motion detection and correction methods, thus further reducing motion sensitivity in MR applications. Magn Reson Med 66:135-143, 2011. (C) 2011 Wiley-Liss, Inc.
Magnetic Resonance In Medicine
DOI : 10.1002/mrm.22797
Assessing The Importance Of An Astrocyte Specific Anaplerotic Enzyme In The Central Nervous System Of Rat2011. 10th European Meeting on Glial Cells in Health and Disease , Prague, CZECH REPUBLIC , Sep 13-17, 2011. p. S109-S110.
High-Resolution Magnetic Resonance Imaging Quantitatively Detects Individual Pancreatic Islets
OBJECTIVE-We studied whether manganese-enhanced high-field magnetic resonance (MR) imaging (MEHFMRI) could quantitatively detect individual islets in situ and in vivo and evaluate changes in a model of experimental diabetes.
DOI : 10.2337/db11-0726
Structural Magnetic Resonance Imaging
Notwithstanding its great success in diagnostic routine and research, structural magnetic resonance imaging (MRI) still faces challenges. In this context, the present thesis studies new approaches to mitigate the motion susceptibility of MRI. Furthermore, it shows new possibilities to prevent inhomogeneities in T1-weighted imaging. Lastly, the performance of different MRI sequences with regard to lesion conspicuity is evaluated in a cohort of early-stage multiple sclerosis (MS) patients. Free-induction-decay (FID) navigators are first established as a novel approach to detect motion using multi-channel MR receive coils. It is demonstrated that a very short sample of the FID suffices to obtain information about the occurrence of head motion. A major advantage of FID navigators – arising from their short duration – is their negligible interference with the actual imaging procedures. This allows their incorporation in various acquisition schemes. In a first proof-of-concept demonstration, the FID navigators are employed in an anatomical imaging sequence. Subsequently, a comprehensive approach for retro- and prospective motion correction in MR diffusion imaging employing FID navigators is presented. Within the scope of T1-weighted imaging, the MP2RAGE sequence is introduced. This novel sequence enables the acquisition of homogeneous T1-weighted images at high and ultra-high fields by cancelling out the bias field which arises from inhomogeneities in the transmission and reception RF fields. In addition, it is shown that the very pure T1-weighted contrast obtained allows the derivation of quantitative T1-maps. Finally, the conspicuity of MS lesions in different routine and non-standard MR image contrasts is investigated in a cohort of ten early-stage MS patients. Thereby, the MP2RAGE sequence is directly applied in a clinical context. Together with a standard T2 measurement, its T1-mapping feature is used to provide a comprehensive picture of MR lesion characteristics in this patient group. An important finding of the study is that routine MS protocols may be considerably improved by employing new acquisition techniques. The insights gained in this study may hence contribute to optimise future clinical MS imaging protocols. To conclude, this thesis introduces different novel techniques to improve structural MRI. Besides the investigation of the theoretical aspects of the presented methods, their application is also evaluated in realistic settings.Lausanne, EPFL, 2011.
DOI : 10.5075/epfl-thesis-5132.
Chronic delivery of antibody fragments using immunoisolated cell implants as a passive vaccination tool
BACKGROUND: Monoclonal antibodies and antibody fragments are powerful biotherapeutics for various debilitating diseases. However, high production costs, functional limitations such as inadequate pharmacokinetics and tissue accessibility are the current principal disadvantages for broadening their use in clinic. METHODOLOGY AND PRINCIPAL FINDINGS: We report a novel method for the long-term delivery of antibody fragments. We designed an allogenous immunoisolated implant consisting of polymer encapsulated myoblasts engineered to chronically release scFv antibodies targeted against the N-terminus of the Aβ peptide. Following a 6-month intracerebral therapy we observed a significant reduction of the production and aggregation of the Aβ peptide in the APP23 transgenic mouse model of Alzheimer's disease. In addition, functional assessment showed prevention of behavioral deficits related to anxiety and memory traits. CONCLUSIONS AND SIGNIFICANCE: The chronic local release of antibodies using immunoisolated polymer cell implants represents an alternative passive vaccination strategy in Alzheimer's disease. This novel technique could potentially benefit other diseases presently treated by local and systemic antibody administration.
DOI : 10.1371/journal.pone.0018268
Matching Pursuit Iterative Dipole Based Filter of Background Fields in Phase Imaging
The information present in the phase of gradient-echo images has opened a new window to look at fine brain anatomy. To obtain high quality phase images depicting small field perturbations produced by tissue susceptibility differences, large slowly spatially varying phase shifts due to air-tissue interfaces have to be removed. Various techniques have been proposed to fit this background field with the field generated by magnetic dipoles that either demand extra information regarding the object, or user input, or have require high number of iterations. In this work, a fast converging method based on an approximate solution of the Matching Pursuit iterative procedure is presented, which regularizes this ill-posed deconvolution problem by exploiting the spatial sparsity of the sources of the background field.2011. International Society for Magnetic Resonance in Medicine (ISMRM) conference , Montreal, Canada , May 7-13, 2011. p. 2664.
Early Predictive Biomarkers for Lesion After Transient Cerebral Ischemia
Background and Purpose—Despite the improving imaging techniques, it remains challenging to predict the outcome early after transient cerebral ischemia. The aim of this study was thus to identify early metabolic biomarkers for outcome prediction. Methods—We modeled transient ischemic attacks and strokes in mice. Using high-field MR spectroscopy, we correlated early changes in the neurochemical profile of the ischemic striatum with histopathologic alterations at a later time point. Results—A significant increase in glutamine was measured between 3 hours and 8 hours after all ischemic events followed by reperfusion independently of the outcome and can thus be considered as an indicator of recent transient ischemia. On the other hand, a reduction of the score obtained by summing the concentrations of N-acetyl aspartate, glutamate, and taurine was a good predictor of an irreversible lesion as early as 3 hours after ischemia. Conclusions—We identified biomarkers of reversible and irreversible ischemic damage, which can be used in an early predictive evaluation of stroke outcome
DOI : 10.1161/STROKEAHA.110.603647
Accelerated MR imaging with spread spectrum encoding
We advocate the use of a novel compressed sensing technique for accelerating the magnetic resonance image acquisition process, coined spread spectrum MR imaging or simply s2MRI. The method resides in pre-modulating the signal of interest by a linear chirp, resulting from the application of quadratic phase profiles, before random k-space under-sampling with uniform average density. The effectiveness of the procedure is theoretically underpinned by the optimization of the coherence between the sparsity and sensing bases. The application of the technique for single coil acquisitions is thoroughly studied by means of numerical simulations as well as phantom and in vivo experiments on a 7T scanner. The corresponding results suggest a favorable comparison with state-of-the-art variable density k-space under-sampling approaches.2011. International Society for Magnetic Resonance in Medicine (ISMRM) conference , Montreal , May 7-13, 2011. p. 2808.