Rolf Gruetter

[140] 129Xe Dynamic Nuclear Polarization Demystified: The Influence of the Glassing Matrix on the Radical Properties

E. Wiström; J.-N. Hyacinthe; T. P. Lê; R. Gruetter; A. Capozzi

[139] Diffusion-weighted SPECIAL improves the detection of J-coupled metabolites at ultrahigh magnetic field

J. Mosso; D. Simicic; B. Lanz; R. Gruetter; C. Cudalbu

[138] Deletion of Crtc1 leads to hippocampal neuroenergetic impairments associated with depressive-like behavior

A. Cherix; C. Poitry-Yamate; B. Lanz; O. Zanoletti; J. Grosse  et al.

[137] Hyperpolarized (1-13C)Alaninamide Is a Multifunctional In Vivo Sensor of Aminopeptidase N Activity, pH, and CO2

A. Radaelli; D. Ortiz; A. Michelotti; M. Roche; R. Hata  et al.

[136] Segmenting electroencephalography wires reduces radiofrequency shielding artifacts in simultaneous electroencephalography and functional magnetic resonance imaging at 7 T

T. P. Lê; R. Gruetter; J. Jorge; Ö. Ipek

[135] Central nervous system and systemic oxidative stress interplay with inflammation in a bile duct ligation rat model of type C hepatic encephalopathy (vol 178, pg 295, 2022)

K. Pierzchala; D. Simicic; A. Sienkiewicz; D. Sessa; S. Mitrea  et al.

[134] [13C]bicarbonate labelled from hyperpolarized [1-13C]pyruvate is an in vivo marker of hepatic gluconeogenesis in fasted state

E. Can; J. A. M. Bastiaansen; D.-L. Couturier; R. Gruetter; H. A. I. Yoshihara  et al.

[133] Central nervous system and systemic oxidative stress interplay with inflammation in a bile duct ligation rat model of type C hepatic encephalopathy

K. Pierzchala; D. Simicic; A. Sienkiewicz; D. Sessa; S. Mitrea  et al.

[132] Probiotics combined with rifaximin influence the neurometabolic changes in a rat model of type C HE

E. Flatt; V. A. McLin; O. Braissant; K. Pierzchala; P. Mastromarino  et al.

[131] Evaluation of the whole auditory pathway using high-resolution and functional MRI at 7T parallel-transmit

S. Da Costa; J. Clement; R. Gruetter; O. Ipek

[130] Radical-free hyperpolarized MRI using endogenously occurring pyruvate analogues and UV-induced nonpersistent radicals

C. C. Zanella; A. Capozzi; H. A. Yoshihara; A. Radaelli; A. L. C. Mackowiak  et al.

[129] Measuring Glycolytic Activity with Hyperpolarized [2H7, U-13C6] D-Glucose in the Naive Mouse Brain under Different Anesthetic Conditions

E. Flatt; B. Lanz; Y. Pilloud; A. Capozzi; M. H. Lerche  et al.

[128] Dipole-Fed Rectangular Dielectric Resonator Antennas for Magnetic Resonance Imaging at 7 T: The Impact of Quasi-Transverse Electric Modes on Transmit Field Distribution

D. Wenz; R. Gruetter

[127] PIRACY: An Optimized Pipeline for Functional Connectivity Analysis in the Rat Brain

Y. Diao; T. Yin; R. Gruetter; I. Jelescu

[126] Hyperpolarized C-13-glucose magnetic resonance highlights reduced aerobic glycolysis in vivo in infiltrative glioblastoma

M. Mishkovsky; O. Gusyatiner; B. Lanz; C. Cudalbu; I. Vassallo  et al.

[125] Excitatory/inhibitory neuronal metabolic balance in mouse hippocampus upon infusion of [U-C-13(6)]glucose

A. Cherix; G. Donati; B. Lizarbe; B. Lanz; C. Poitry-Yamate  et al.

[124] Late post‐natal neurometabolic development in healthy male rats using 1 H and 31 P Magnetic Resonance Spectroscopy

V. Račkayová; D. Simicic; G. Donati; O. Braissant; R. Gruetter  et al.

[123] The relationship between EEG and fMRI connectomes is reproducible across simultaneous EEG-fMRI studies from 1.5T to 7T

J. Wirsich; J. Jorge; G. R. Iannotti; E. A. Shamshiri; F. Grouiller  et al.

[122] Brain NAD Is Associated With ATP Energy Production and Membrane Phospholipid Turnover in Humans

B. Cuenoud; O. Ipek; M. Shevlyakova; M. Beaumont; S. C. Cunnane  et al.

[121] Contribution of macromolecules to brain H-1 MR spectra: Experts' consensus recommendations

C. Cudalbu; K. L. Behar; P. K. Bhattacharyya; W. Bogner; T. Borbath  et al.

[120] Magnetic resonance spectroscopy in the rodent brain: Experts' consensus recommendations

B. Lanz; A. Abaei; O. Braissant; I.-Y. Choi; C. Cudalbu  et al.

[119] 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

A. Radaelli; H. A. Yoshihara; H. Nonaka; S. Sando; J. H. Ardenkjaer-Larsen  et al.

[118] B(0)shimming for in vivo magnetic resonance spectroscopy: Experts' consensus recommendations

C. Juchem; C. Cudalbu; R. A. de Graaf; R. Gruetter; A. Henning  et al.

[117] Combined deletion of Glut1 and Glut3 impairs lung adenocarcinoma growth

C. Contat; P.-B. Ancey; N. Zangger; S. Sabatino; J. Pascual  et al.

[116] Metabolic and perfusion responses to acute hypoglycemia in the rat cortex: A non-invasive magnetic resonance approach

H. Lei; R. Gruetter

[115] The Appearance of the Warburg Effect in the Developing Avian Eye Characterized In Ovo: How Neurogenesis Can Remodel Neuroenergetics

A. Cherix; L. Brodier; C. Poitry-Yamate; J.-M. Matter; R. Gruetter

[114] In vivo detection of d-amino acid oxidase with hyperpolarized d-[1-C-13]alanine

A. Radaelli; R. Gruetter; H. A. I. Yoshihara

[113] Impact of aerobic exercise type on blood flow, muscle energy metabolism, and mitochondrial biogenesis in experimental lower extremity artery disease

M. Pellegrin; K. Bouzourène; J.-F. Aubert; C. Bielmann; R. Gruetter  et al.

[112] Glutamine-to-glutamate ratio in the nucleus accumbens predicts effort-based motivated performance in humans

A. V. I. Strasser; G. Luksys; L. Xin; M. Pessiglione; R. Gruetter  et al.

[111] Metabolic signature in nucleus accumbens for anti-depressant-like effects of acetyl-L-carnitine

A. Cherix; T. Larrieu; J. Grosse; J. Rodrigues; B. McEwen  et al.

[110] Glucose transporter 2 mediates the hypoglycemia-induced increase in cerebral blood flow

H. Lei; F. Preitner; G. Labouebe; R. Gruetter; B. Thorens

[109] N-Acetyl-Cysteine Supplementation Improves Functional Connectivity Within the Cingulate Cortex in Early Psychosis: A Pilot Study

E. Mullier; T. Roine; A. Griffa; L. Xin; P. S. Baumann  et al.

[108] Evolution of the neurochemical profiles in the G93A-SOD1 mouse model of amyotrophic lateral sclerosis

H. Lei; E. A. Dirren; C. Poitry-Yamate; B. Schneider; R. Gruetter  et al.

[107] Capturing the spatiotemporal dynamics of self-generated, task-initiated thoughts with EEG and fMRI

L. Bréchet; D. Brunet; G. Birot; R. Gruetter; C. M. Michel  et al.

[106] A combined 32‐channel receive‐loops/8‐channel transmit‐dipoles coil array for whole‐brain MR imaging at 7T

J. Clément; R. Gruetter; Ö. Ipek

[105] High-fat diet consumption alters energy metabolism in the mouse hypothalamus

B. Lizarbe; A. Cherix; J. M. N. Duarte; J.-R. Cardinaux; R. Gruetter

[104] A human cerebral and cerebellar 8-channel transceive RF dipole coil array at 7T

J. D. Clément; R. Gruetter; Ö. Ipek

[103] Multi-slice passband bSSFP for human and rodent fMRI at ultra-high field

O. Reynaud; A. R. da Silva; R. Gruetter; I. O. Jelescu

[102] Methodological consensus on clinical proton MRS of the brain: Review and recommendations

M. Wilson; O. Andronesi; P. B. Barker; R. Bartha; A. Bizzi  et al.

[101] Improved off‐resonance phase behavior using a phase‐inverted adiabatic half‐passage pulse for 13 C MRS in humans at 7 T

E. Serés Roig; L. Xin; D. Gallichan; V. Mlynarik; R. Gruetter

[100] Nucleus accumbens neurochemistry in human anxiety: A 7 T 1H-MRS study

A. Strasser; L. Xin; R. Gruetter; C. Sandi

[99] Alterations of Brain Energy Metabolism in Type 2 Diabetic Goto-Kakizaki Rats Measured In Vivo by (13)C Magnetic Resonance Spectroscopy

F.-M. Girault; S. Sonnay; R. Gruetter; J. M. N. Duarte

[98] Investigating the variability of cardiac pulse artifacts across heartbeats in simultaneous EEG-fMRI recordings: A 7T study

J. Jorge; C. Bouloc; L. Bréchet; C. M. Michel; R. Gruetter

[97] Metabolite concentration changes associated with positive and negative BOLD responses in the human visual cortex: A functional MRS study at 7 Tesla

Y. Boillat; L. Xin; W. van der Zwaag; R. Gruetter

[96] Impact of Caffeine Consumption on Type 2 Diabetes-Induced Spatial Memory Impairment and Neurochemical Alterations in the Hippocampus

J. M. N. Duarte; C. Skoug; H. B. Silva; R. A. Carvalho; R. Gruetter  et al.

[95] Feasibility of in vivo measurement of glucose metabolism in the mouse hypothalamus by (1) H-[(13) C] MRS at 14.1T

B. Lizarbe Serra; H. Lei; J. M. das Neves Duarte; B. Lanz; A. Cherix  et al.

[94] Probing cardiac metabolism by hyperpolarized 13C MR using an exclusively endogenous substrate mixture and photo-induced nonpersistent radicals

J. A. M. Bastiaansen; H. A. I. Yoshihara; A. Capozzi; J. Schwitter; R. Gruetter  et al.

[93] Nutritional Ketosis Increases NAD+/NADH Ratio in Healthy Human Brain: An in Vivo Study by 31P-MRS

L. Xin; Ö. Ipek; M. Beaumont; M. Shevlyakova; N. Christinat  et al.

[92] Cannabis use in early psychosis is associated with reduced glutamate levels in the prefrontal cortex

S. Rigucci; L. Xin; P. Klauser; P. S. Baumann; L. Alameda  et al.

[91] Clinical Neuroimaging Using 7 T MRI: Challenges and Prospects

M. I. Vargas; P. Martelli; L. Xin; O. Ipek; F. Grouiller  et al.

[90] Increased hepatic fatty acid polyunsaturation precedes ectopic lipid deposition in the liver in adaptation to high-fat diets in mice

A. F. Soares; J. M. das Neves Duarte; R. Gruetter

[89] Astrocytic and neuronal oxidative metabolism are coupled to the rate of glutamate-glutamine cycle in the tree shrew visual cortex

S. Sonnay; J. Poirot; N. Just; A.-C. Clerc; R. Gruetter  et al.

[88] N-acetylcysteine add-on treatment leads to an improvement of fornix white matter integrity in early psychosis: a double-blind randomized placebo-controlled trial

P. Klauser; L. Xin; M. Fournier; A. Griffa; M. Cleusix  et al.

[87] 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

M. Lai; B. Lanz; C. Poitry-Yamate; J. F. Romero; C. M. Berset  et al.

[86] 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

M. Lai; I. Vassallo; B. Lanz; C. Poitry-Yamate; M.-F. Hamou  et al.

[85] Mapping and characterization of positive and negative BOLD responses to visual stimulation in multiple brain regions at 7T

J. Jorge; p. figueiredo; R. Gruetter; W. Van der Zwaag

[84] Energy metabolism in the rat cortex under thiopental anaesthesia measured

S. Sonnay; J. M. N. Duarte; N. Just; R. Gruetter

[83] How Energy Metabolism Supports Cerebral Function: Insights from 13C Magnetic Resonance Studies In vivo

S. Sonnay; R. Gruetter; J. M. N. Duarte

[82] Influence of physiological noise on accelerated 2D and 3D resting state functional MRI data at 7 T

O. Reynaud; J. Jorge; R. Gruetter; J. P. Marques; W. van der Zwaag

[81] Sexual dimorphism in hepatic lipids is associated with the evolution of metabolic status in mice

A. F. Soares; J. Paz-Montoya; H. Lei; M. Moniatte; R. Gruetter

[80] Glycogen Supercompensation in the Rat Brain After Acute Hypoglycemia is Independent of Glucose Levels During Recovery

J. M. N. Duarte; F. D. Morgenthaler; R. Gruetter

[79] Prospective head motion correction using FID-guided on-demand image navigators

M. Waszak; P. Falkovskiy; T. Hilbert; G. Bonnier; B. Maréchal  et al.

[78] Technical and experimental features of Magnetic Resonance Spectroscopy of brain glycogen metabolism

A. F. Soares; R. Gruetter; H. Lei

[77] Diffusion-weighted MRS of acetate in the rat brain

M. Dehghani; N. Kunz; B. Lanz; H. A. I. Yoshihara; R. Gruetter

[76] Hierarchical status predicts behavioral vulnerability and nucleus accumbens metabolic profile following chronic social defeat stress.

T. Larrieu; A. Cherix; A. Duque; J. Rodrigues; H. Lei  et al.

[75] 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

A. Corcoba; R. Gruetter; K. Q. Do; J. M. N. Duarte

[74] Progress towards in vivo brain (13)C-MRS in mice: Metabolic flux analysis in small tissue volumes

M. Lai; R. Gruetter; B. Lanz

[73] Studying cyto and myeloarchitecture of the human cortex at ultra-high field with quantitative imaging: R1, R⁎2 and susceptibility

J. P. Marques; D. Khabipova; R. Gruetter

[72] Genetic Polymorphism Associated Prefrontal Glutathione and Its Coupling With Brain Glutamate and Peripheral Redox Status in Early Psychosis

L. Xin; R. Mekle; M. Fournier; P. S. Baumann; C. Ferrari  et al.

[71] Refined Analysis of Brain Energy Metabolism Using In Vivo Dynamic Enrichment of 13C Multiplets

M. Dehghani M; B. Lanz; J. M. N. Duarte; N. Kunz; R. Gruetter

[70] Glutathione deficit affects the integrity and function of the fimbria/fornix and anterior commissure in mice: relevance for schizophrenia

A. Corcoba; P. Steullet; J. M. N. Duarte; Y. Van de Looij; A. Monin  et al.

[69] Three-dimensional echo planar imaging with controlled aliasing: A sequence for high temporal resolution functional MRI

M. Narsude; D. Gallichan; W. Van Der Zwaag; R. Gruetter; J. P. Marques

[68] Simultaneous and interleaved acquisition of NMR signals from different nuclei with a clinical MRI scanner

M. Meyerspeer; A. W. Magill; A. Kuehne; R. Gruetter; E. Moser  et al.

[67] Hyperpolarized 6Li as a probe for hemoglobin oxygenation level

R. Balzan; M. Mishkovsky; Y. Simonenko; R. B. van Heeswijk; R. Gruetter  et al.

[66] 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

S. Sonnay; J. M. Duarte; N. Just; R. Gruetter

[65] 3D T 2-weighted imaging at 7T using dynamic kT-points on single-transmit MRI systems

F. Eggenschwiler; K. R. O'Brien; D. Gallichan; R. Gruetter; J. P. Marques

[64] Early detection of human glioma sphere xenografts in mouse brain using diffusion MRI at 14.1 T

P. Porcari; M. E. Hegi; H. Lei; -F. Hamou; I. Vassallo  et al.

[63] Quantitative activity-induced manganese-dependent MRI for characterizing cortical layers in the primary somatosensory cortex of the rat

M. Auffret; I. Samim; M. Lepore; R. Gruetter; N. Just

[62] Retrospective correction of involuntary microscopic head movement using highly accelerated fat image navigators (3D FatNavs) at 7T

D. Gallichan; J. P. Marques; R. Gruetter

[61] Direct noninvasive estimation of myocardial tricarboxylic acid cycle flux in vivo using hyperpolarized 13C magnetic resonance

J. Bastiaansen; T. Cheng; H. Lei; R. Gruetter; A. Comment

[60] Stroking or Buzzing? A Comparison of Somatosensory Touch Stimuli Using 7 Tesla fMRI

W. van der Zwaag; R. Gruetter; R. Martuzzi

[59] Physiological noise in human cerebellar fMRI

W. Van Der Zwaag; J. Jorge; D. Butticaz; R. Gruetter

[58] Brain energy metabolism measured by 13C magnetic resonance spectroscopy in vivo upon infusion of [3-13C]lactate

J. M. Duarte; F.-M. Girault; R. Gruetter

[57] 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

A. F. Soares; H. Lei; R. Gruetter

[56] Towards high-quality simultaneous EEG-fMRI at 7T: Detection and reduction of EEG artifacts due to head motion

J. Jorge; F. Grouiller; R. Gruetter; W. Van Der Zwaag; P. Figueiredo

[55] Fast low-specific absorption rate B0-mapping along projections at high field using two-dimensional radiofrequency pulses

O. Reynaud; D. Gallichan; B. Schaller; R. Gruetter

[54] Correcting surface coil excitation inhomogeneities in single-shot SPEN MRI

R. Schmidt; M. Mishkovsky; J.-N. Hyacinthe; N. Kunz; R. Gruetter  et al.

[53] A Modulated Closed Form solution for Quantitative Susceptibility Mapping - A thorough evaluation and comparison to iterative methods based on edge prior knowledge

D. Khabipova; Y. Wiaux; R. Gruetter; J. P. Marques

[52] Single acquisition electrical property mapping based on relative coil sensitivities: A proof-of-concept demonstration

J. P. Marques; D. K. Sodickson; O. Ipek; C. M. Collins; R. Gruetter

[51] A double-quadrature radiofrequency coil design for proton-decoupled carbon-13 magnetic resonance spectroscopy in humans at 7T

E. Serés Roig; A. W. Magill; G. Donati; M. Meyerspeer; L. Xin  et al.

[50] In Vivo Longitudinal (1)H MRS Study of Transgenic Mouse Models of Prion Disease in the Hippocampus and Cerebellum at 14.1 T

C. Cudalbu; M. Craveiro; V. Mlynárik; J. Bremer; A. Aguzzi  et al.

[49] Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients

A. Monin; P. Baumann; A. Griffa; L. Xin; R. Mekle  et al.

[48] Imaging of prolonged BOLD response in the somatosensory cortex of the rat

S. Sonnay; N. Just; J. M. N. Duarte; R. Gruetter

[47] Distinct contributions of Brodmann areas 1 and 2 to body ownership

R. Martuzzi; W. Van Der Zwaag; S. Dieguez; A. Serino; R. Gruetter  et al.

[46] Simultaneous EEG–fMRI at ultra-high field: Artifact prevention and safety assessment

J. Jorge; F. Grouiller; Ö. Ipek; R. Stoermer; C. M. Michel  et al.

[45] GDH-Dependent Glutamate Oxidation in the Brain Dictates Peripheral Energy Substrate Distribution

M. Karaca; F. Frigerio; S. Migrenne; J. Martin-Levilain; D. Skytt  et al.

[44] Parallel imaging with phase scrambling

M. Zaitsev; G. Schultz; J. Hennig; R. Gruetter; D. Gallichan

[43] Assessment of metabolic fluxes in the mouse brain in vivo using (1)H-[(13)C] NMR spectroscopy at 14.1 Tesla

L. Xin; B. Lanz; H. Lei; R. Gruetter

[42] Experimental peripheral arterial disease: new insights into muscle glucose uptake, macrophage, and T-cell polarization during early and late stages

M. Pellegrin; K. Bouzourène; C. Poitry-Yamate; V. Mlynarik; F. Feihl  et al.

[41] In vivo brain macromolecule signals in healthy and glioblastoma mouse models: 1H magnetic resonance spectroscopy, post-processing and metabolite quantification at 14.1 T

M. Craveiro; V. Clément-Schatlo; D. Marino; R. Gruetter; C. Cudalbu

[40] Definition and quantification of acute inflammatory white matter injury in the immature brain by MRI/MRS at high magnetic field

G. A. Lodygensky; N. Kunz; E. Perroud; E. Somm; V. Mlynarik  et al.

[39] Longitudinal neurochemical modifications in the aging mouse brain measured in vivo by 1H magnetic resonance spectroscopy

J. M. N. Duarte; K. Q. Do; R. Gruetter

[38] Improving T2 -weighted imaging at high field through the use of kT -points

F. Eggenschwiler; K. R. O'Brien; R. Gruetter; J. P. Marques

[37] Protective effects of maternal nutritional supplementation with lactoferrin on growth and brain metabolism

E. Somm; P. Larvaron; Y. Van De Looij; A. Toulotte; A. Chatagner  et al.

[36] Phase-based manganese enhanced MRI, a new methodology to enhance brain cytoarchitectural contrast and study manganese uptake

R. Maddage; J. P. Marques; R. Gruetter

[35] Are glutamate and lactate increases ubiquitous to physiological activation? A 1H functional MR spectroscopy study during motor activation in human brain at 7Tesla

B. Schaller; L. Xin; K. O‘Brien; A. Magill; R. Gruetter

[34] Is the macromolecule signal tissue-specific in healthy human brain? A 1H MRS study at 7 tesla in the occipital lobe

B. Schaller; L. Xin; R. Gruetter

[33] In vivo quantification of neuro-glial metabolism and glial glutamate concentration using 1H-[13C] MRS at 14.1T

B. Lanz; L. Xin; P. Millet; R. Gruetter

[32] Hyperpolarized 13C lactate as a substrate for in vivo metabolic studies in skeletal muscle

J. A. M. Bastiaansen; H. A. I. Yoshihara; Y. Takado; R. Gruetter; A. Comment

[31] Non-invasive diagnostic biomarkers for estimating the onset time of permanent cerebral ischemia

C. Berthet; L. Xin; L. Buscemi; C. Benakis; R. Gruetter  et al.

[30] Optimized MEGA-SPECIAL for in vivo glutamine detection in the rat brain at 14.1 T

M. Craveiro; C. Cudalbu; V. Mlynárik; R. Gruetter

[29] Improved temporal resolution for functional studies with reduced number of segments with three-dimensional echo planar imaging

M. Narsude; W. Van Der Zwaag; T. Kober; R. Gruetter; J. P. Marques

[28] Image-Derived Input Function from the Vena Cava for 18F-FDG PET Studies in Rats and Mice

B. Lanz; C. Poitry-Yamate; R. Gruetter

[27] Human finger somatotopy in areas 3b, 1, and 2: A 7T fMRI study using a natural stimulus

R. Martuzzi; W. van der Zwaag; J. Farthouat; R. Gruetter; O. Blanke

[26] Multi-modal assessment of long-term erythropoietin treatment after neonatal hypoxic-ischemic injury in rat brain

Y. van de Looij; A. Chatagner; C. Quairiaux; R. Gruetter; P. S. Hüppi  et al.

[25] MRS glucose mapping and PET joining forces: Re-evaluation of the lumped constant in the rat brain under isoflurane anaesthesia

M. F. Alf; J. M. N. Duarte; H. Lei; S. D. Krämer; V. Mlynarik  et al.

[24] An improved trap design for decoupling multinuclear RF coils

M. Meyerspeer; E. Serés Roig; R. Gruetter; A. W. Magill

[23] Clinical Proton MR Spectroscopy in Central Nervous System Disorders

G. Öz; J. R. Alger; P. B. Barker; R. Bartha; A. Bizzi  et al.

[22] Quantification of the neurochemical profile using simulated macromolecule resonances at 3 T

B. Schaller; L. Xin; C. Cudalbu; R. Gruetter

[21] Hepatic glucose sensing is required to preserve β cell glucose competence

P. Seyer; D. Vallois; C. Poitry-Yamate; F. Schütz; S. Metref  et al.

[20] Proton T(1) relaxation times of metabolites in human occipital white and gray matter at 7 T

L. Xin; B. Schaller; V. Mlynarik; H. Lu; R. Gruetter

[19] Investigation of field and diffusion time dependence of the diffusion-weighted signal at ultrahigh magnetic fields

N. Kunz; S. V. Sizonenko; P. S. Hüppi; R. Gruetter; Y. van de Looij

[18] 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

J. Bastiaansen; T. Cheng; M. Mishkovsky; J. M. das Neves Duarte; A. Comment  et al.

[17] Net increase of lactate and glutamate concentration in activated human visual cortex detected with magnetic resonance spectroscopy at 7 tesla

B. Schaller; R. Mekle; L. Xin; N. Kunz; R. Gruetter

[16] Unedited in vivo detection and quantification of gamma-aminobutyric acid in the occipital cortex using short-TE MRS at 3 T

J. Near; J. Andersson; E. Maron; R. Mekle; R. Gruetter  et al.

[15] Feasibility of direct mapping of cerebral fluorodeoxy-D-glucose metabolism in situ at subcellular resolution using soft X-ray fluorescence

C. Poitry-Yamate; A. Gianoncelli; B. Kaulich; G. Kourousias; A. W. Magill  et al.

[14] Feasibility and electromagnetic compatibility study of the ClearPEM front-end electronics for simultaneous PET-MR imaging

D. Neves; J. André; R. Bugalho; R. Gruetter; A. Magill  et al.

[13] The C57BL/6J Mouse Exhibits Sporadic Congenital Portosystemic Shunts

C. Cudalbu; V. A. Mclin; H. Lei; J. M. N. Duarte; A.-L. Rougemont  et al.

[12] Which prior knowledge? Quantification of in vivo brain (13) C MR spectra following (13) C glucose infusion using AMARES

B. Lanz; J. M. N. Duarte; N. Kunz; V. Mlynárik; R. Gruetter  et al.

[11] Characterization of sustained BOLD activation in the rat barrel cortex and Neurochemical consequences

N. Just; L. Xin; H. Frenkel; R. Gruetter

[10] Single spin-echo T 2 relaxation times of cerebral metabolites at 14.1 T in the in vivo rat brain

L. Xin; G. Gambarota; C. Cudalbu; V. Mlynárik; R. Gruetter

[9] Direct mapping of 19F in 19FDG-6P in brain tissue at subcellular resolution using soft X-ray fluorescence

C. Poitry-Yamate; A. Gianoncelli; G. Kourousias; B. Kaulich; M. Lepore  et al.

[8] Glutamatergic and GABAergic energy metabolism measured in the rat brain by 13C NMR spectroscopy at 14.1 T

J. M. N. Duarte; R. Gruetter

[7] Metabolic Flux and Compartmentation Analysis in the Brain In vivo

B. Lanz; R. Gruetter; J. M. N. Duarte

[6] 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

P. Coune; M. Craveiro; M. Gaugler; V. Mlynárik; B. Schneider  et al.

[5] Brain Glucose Transport and Phosphorylation Under Acute Insulin-Induced Hypoglycemia in Mice: An 18F-FDG PET Study

M. F. Alf; J. M. N. Duarte; R. Schibli; R. Gruetter; S. D. Kramer

[4] 3D Residual Eddy Current Field Characterisation: applied to Diffusion Weighted Magnetic Resonance Imaging

K. O'Brien; A. Daducci; N. Kickler; F. Lazeyras; R. Gruetter  et al.

[3] 9.4-14.1 T small-animal PET-MR imaging: Feasibility analysis of LYSO APD readout via long signal lines

J. A. Neves; R. Bugalho; R. Gruetter; A. W. Magill; C. Ortigao  et al.

[2] New Developments and Applications of the MP2RAGE Sequence - Focusing the Contrast and High Spatial Resolution R1 Mapping

J. P. Marques; R. Gruetter

[1] Digit somatotopy in the human cerebellum: A 7T fMRI study

W. van der Zwaag; R. Kusters; A. Magill; R. Gruetter; R. Martuzzi  et al.

Fast Quantification of Creatine Kinase Activity by Phosphorus Magnetic Resonance Fingerprinting

M. S. Widmaier / R. Gruetter; L. Xin (Dir.)

A novel fast 3D-31P-B+1 mapping method called the frequency-selective Double-AngleMethod (fDAM) has been developed. This method integrates a 3D weighted stack of spiral gradient echo acquisitions with a frequency-selective pulse to efficiently map B+1 fields based on the phosphocreatine (PCr) signal at 7 T. The protocol has been optimized using simulations and validated through both phantom experiments and skeletal muscle applications. Results showed that fDAMnot only achieves a high correlation (r = 0.94) with the classical DAM (cDAM) but also provides faster and more extensive coverage. 3D-31P-B+1 mapping of the human calf muscle was completed in just 11min using fDAM compared to 24 minutes using cDAM. Furthermore, the first full-brain 31P 3D B+1 mapping was achieved in 13 minutes using a 1 Tx/32 Rx coil. These findings show that fDAM is able to provide B+1 mapping for accurate transmit field correction within the same scanning session of other 31P-MRS/I applications. A new magnetization transfer (MT)-31P-Magnetic resonance fingerprinting (MRF) approach was developed to measure the creatine kinase (CK) metabolic reaction rate (kCK) between PCr and adenosine triphosphate (ATP) in the human brain. This method extends the MRF framework to overcome conventional challenges in 31P-Measurement, such as long scan times and high specific absorption rates. A novel nested iteration interpolation method (NIIM) was introduced to efficiently handle the growing complexity of the multiparametric dictionary matching process. The combination ofMT-31P-MRF with NIIM allows for accurate estimations of the longitudinal relaxation times T1PCr and T1ATP, ATP/PCr concentration ratios Cr, B1, off resonance foff and kCK, showing excellent agreement with existing techniques like the exchange kinetics by band inversion transfer (EBIT) method and values reported in literature. This method demonstrated a significant reduction in scan time, from 17 minutes 4 seconds using EBIT to just 4 minutes 15 seconds with MT-31P-MRF, while maintaining similar or better reproducibility (with coefficients of variation less than 12%). Further advancing this approach, the MT-31P-MRF was extended to perform 3D CreatineKinase Imaging (CKI), delivering the first whole-brain kCK maps. Whole-brain CKI were acquired on a clinical 7T MRI scanner, generating high-resolution CK ratemaps in 49minutes 30 seconds. Further, within-session reproducibility assessment showed amean coefficient of variation below 11% and suggested that scans could be completed within 25minutes. In addition to kCK mapping, CKI provided simultaneous mapping of Cr, T1PCr values, and phosphorus-based B0 maps with a spatial resolution of 7.2 × 7.2 × 20mm3. In a proof-of-concept functional study, functional CKI (fCKI) was used to demonstrate CK activation in the brain's visual cortex in response to visual stimulation, revealing a mean 17% increase in CK reaction rates in the visual cortex. This represents the first 3D CK activation map in the human brain, providing a novel functional imaging methodology to gain insights into brain functional bioenergetics

129Xe Dynamic Nuclear Polarization Demystified: The Influence of the Glassing Matrix on the Radical Properties

E. Wiström; J.-N. Hyacinthe; T. P. Lê; R. Gruetter; A. Capozzi

129Xe dissolution dynamic nuclear polarization (DNP) is a controversial topic. The gold standard technique for hyperpolarized xenon magnetic resonance imaging (MRI) is spin exchange optical pumping, which received FDA approval in 2022. Nevertheless, the versatility of DNP for enhancing the signal of any NMR active nucleus might provide new perspectives for hyperpolarized 129Xe NMR/MRI. Initial publications about 129Xe DNP underlined the increased complexity in the sample preparation and lower polarization levels when compared to more conventional 13C-labeled molecules, at same experimental conditions, despite very close gyromagnetic ratios. Herein, we introduce, using a Custom Fluid Path system, a user-friendly and very robust sample preparation method. Moreover, investigating the radical properties at real DNP conditions by means of LOngitudinal Detected Electron Spin Resonance, we discovered a dramatic shortening of the electron spin longitudinal relaxation time (T1e) of nitroxyl radicals in xenon DNP samples’ matrices, with respect to more commonly used water:glycerol ones. Mitigating those challenges through microwave frequency modulation, we achieved over 20% 129Xe polarization without employing any deuterated solvent.

DOI : 10.1021/acs.jpclett.4c00177

Diffusion-weighted SPECIAL improves the detection of J-coupled metabolites at ultrahigh magnetic field

J. Mosso; D. Simicic; B. Lanz; R. Gruetter; C. Cudalbu

PurposeTo improve the detection and subsequent estimation of the diffusion properties of strongly J-coupled metabolites in diffusion-weighted MRS (DWS).MethodsA new sequence for single-voxel diffusion-weighted 1H MR spectroscopy, named DW-SPECIAL, is proposed. It combines the semi-adiabatic SPECIAL sequence with a stimulated echo diffusion block. Acquisitions with DW-SPECIAL and STE-LASER, the current gold standard for rodent DWS experiments at high fields, were performed at 14.1T on phantoms and in vivo on the rat brain. The apparent diffusion coefficient and intra-stick diffusivity (Callaghan's model, randomly-oriented sticks) were fitted and compared between the sequences for glutamate, glutamine, myo-inositol, taurine, total NAA, total Cho, total Cr, and the macromolecules.ResultsThe shorter TE achieved with DW-SPECIAL (18 ms against 33 ms with STE-LASER) substantially limited the metabolites' signal loss caused by J-evolution. In addition, DW-SPECIAL preserved the main advantages of STE-LASER: absence of cross-terms, diffusion time during a stimulated echo, and limited sensitivity to B1 inhomogeneities. In vivo, compared to STE-LASER, DW-SPECIAL yielded the same spectral quality and reduced the Cramer Rao Lower Bounds for J-coupled metabolites, irrespective of the b-value. DW-SPECIAL also reduced the SD of the metabolites' diffusion estimates based on individual animal fitting without loss of accuracy compared to the fit on the averaged decay.ConclusionWe conclude that due to its reduced TE, DW-SPECIAL can serve as an alternative to STE-LASER when strongly J-coupled metabolites like glutamine are investigated, thereby extending the range of accessible metabolites in the context of DWS acquisitions.

DOI : 10.1002/mrm.29805

Robust gamma-aminobutyric acid and energy metabolism measurements by proton and phosphorus magnetic resonance spectroscopy and fingerprinting

S. Lim / R. Gruetter; L. Xin (Dir.)

Magnetic resonance spectroscopy (MRS) is the only technique that can detect endogenous metabolites directly and non-invasively in vivo. It allows to identify different metabolites and analyze the dynamic neurochemical processes in the brain, skeletal muscle, and other organs. In this thesis, new acquisition methods are developed in order to improve the robustness of data acquisition and to reduce the scanning duration in human at 7T. gamma-aminobutyric acid (GABA) is a primary inhibitory neurotransmitter which plays a key role to control brain activities associated with normal brain functions and the pathophysiology of disease. However, GABA signal is overlapped with more abundant metabolites, hindering its direct measurement. At ultra-high field, even with the improved SNR and spectral dispersion, it is still challenging to quantify GABA directly using a non-editing short echo time (TE) method. MEGA-sSPECIAL sequence is introduced for improved GABA measurement in the brain. The motor and medial prefrontal cortices were selected considering different GABA concentrations between the two areas. The test-retest reproducibility of the method was compared with that of short-TE measurement with the same localization. Knowledge of relaxation time is not only important for the optimization of acquisition parameters but also for the investigation of alterations in tissue microstructure integrity. Magnetic resonance fingerprinting (MRF) is a novel technique to acquire multi-parametric and quantitative data simultaneously by using varying flip angle, repetition time, and/or TE patterns. Although it has been successfully implemented in clinical studies, it has never been adapted for 31P metabolite acquisition at 7T in the human brain. Therefore, the feasibility of MRF application to T1 and T2 of 31P metabolites measurements is explored in the thesis. Phosphocreatine, Adenosine triphosphate (ATP), and creatine kinase (CK) play key roles in intracellular energy buffering and transport. The energy is needed for various processes in organisms and living cells including intracellular signaling, DNA and RNA synthesis, and muscle contraction. 31P MRS is a unique tool to measure the CK reaction rate constant (kCK) via magnetization transfer, providing important insight into energetics in the brain, muscle, and heart. However, it suffers from low SNR and long acquisition time. In order to overcome the challenges, a novel approach is suggested to acquire 3D CK exchange rate constants map using MRF. High spatial resolution with the minimum acquisition time was achieved using a stack-of-spiral trajectory. The preliminary results obtained from the skeletal muscle are presented in this thesis. In conclusion, the MEGA-sSPECIAL sequence showed more robust GABA quantification results in both of the brain regions than the short-TE method, suggesting a capability to detect small alterations in GABA levels. Fast and simultaneous measurements of T1 and T1 relaxation times of 31P metabolites were enabled by 31P MRF by shortening the acquisition time by 1.7-fold in comparison with inversion recovery and multi-TE techniques. Lastly, the feasibility of 3D kCK mapping by 31P MRF was investigated for the first time with accelerated spatial encoding, achieving 3 min 16 s of acquisition time in the skeletal muscle, paving the way for studying energy metabolism in future clinical and research studies.

New insights into rodent brain microstructure and metabolism in hepatic encephalopathy

J. J. Mosso / R. Gruetter; C. R. Cudalbu (Dir.)

Type C hepatic encephalopathy (HE) is a severe neuropsychiatric complication of chronic liver disease, for which the prognosis is poor in the absence of liver transplantation. Cirrhosis in type C HE leads to a toxic accumulation of ammonia in the blood, which will eventually travel to the brain and adversely affect its structure and function. However, the biochemical mechanisms underpinning neurological and cognitive dysfunctions are intertwined and still incompletely understood. First, it remains unclear how brain cells morphology is affected by the ammonia-induced glutamine increase and osmotic stress in HE. In the bile-duct ligated (BDL) rat model of type C HE, alterations of neurons and astrocytes' shape have been observed ex vivo by histology, but these observations were until now not replicated in vivo. Magnetic resonance (MR) spectroscopy (MRS) at ultra-high field is a powerful tool to probe metabolism in vivo, and can, with the insertion of diffusion gradients, in addition be sensitized to probe cell-specific microstructure. In this thesis, diffusion-weighted MR spectroscopy (dMRS) and imaging (dMRI) experiments were conducted at 14.1T in the developing brain of the BDL rat model of type C HE. The acquisition was optimized to measure the cerebellum, a challenging brain region due to motion and the presence of fat, but of particular vulnerability in HE. Analysed jointly through cell-specific biophysical modelling, dMRS and dMRI probed faster metabolite diffusivities and faster intra-neurite/intra-axon water diffusivity in cerebellar white and grey matter of BDL rats compared to control rats. These observations point towards an alteration of cell density and/or of neurite network complexity and reorient the debate from the restrictive hypothesis of astrocytes swelling to the wider one of multi-cellular microstructure alterations in type C HE. The dMRS acquisition was further optimized with the implementation of a new sequence, DW-SPECIAL. The latter improved the detection and subsequent estimation of the diffusion properties of strongly J-coupled metabolites such as glutamine, of particular interest in the study of HE. A post-processing denoising technique based on the Marchenko Pastur principal component analysis method (MP-PCA) was also tested on simulated, rodent and human dMRS data. MP-PCA denoising yielded both valuable and adverse features specific to the nature of the input data, an effect for which a detailed description was provided and which should be carefully considered. Second, conflicting results on brain energy metabolism alterations in type C HE have been previously reported. Positron emission tomography (PET) is an imaging modality that enables the study of glucose uptake, following the conversion of fluorodeoxyglucose (FDG) in the first steps of the glycolysis in vivo. In this thesis, a new preclinical FDG PET methodology was implemented to compute quantitative 3D maps of the regional cerebral metabolic rate of glucose (CMRglc) from a labelling steady-state PET image of the brain and an image-derived input function. A 2-fold lower CMRglc brain glucose uptake was observed in the hippocampus and cerebellum of the BDL rats. Combined with MRS, it provided for the first time local and quantitative information on both brain glucose uptake and neurometabolic profile alterations in a ratmodel of type C HE. The quantitative approach also showed its strength when comparing groups of animals with divergent physiology.

Enabling Stroke Theranostics with Hyperpolarized Magnetic Resonance

T. P. K. Lê / R. Gruetter; J.-N. Hyacinthe (Dir.)

The severe social and economic burden of stroke is a strong motivation for the exploration of innovative medical approaches. In this context, magnetic resonance (MR) of hyperpolarized (HP) molecular agents via dissolution dynamic nuclear polarization (dDNP) allows tracking their metabolic fate in vivo. This may not only provide novel insights into the underlying metabolic mechanisms, but also pave the way to a theranostic approach for stroke when applied to neuroprotective agents. This thesis focuses on the development of novel theranostic approaches to acute ischemic stroke based on HP neuroprotective agents, specifically [1-13C] lactate and [1-13C] pyruvate, in the preclinical setting. To achieve this goal, it entails two parallel aspects: exploring their aptitude as molecular biomarkers for stroke, and reinforcing the exploitation of this potential by optimizing technical and methodological aspects of HP MR experiments. The dynamics of HP lactate and pyruvate metabolism were quantified via global MR spectroscopic measurements and kinetic modeling. Both substrates underscored their potential as biomarkers for acute ischemic stroke, showing distinct biochemical transport and metabolism in a mouse model of stroke compared to healthy animals. Although lactate is more challenging to acquire as a result of lower polarization and metabolism than pyruvate, it is of greater interest in theranostics with better demonstrated neuroprotective effects. The effects of the nitroxyl radical TEMPOL, a dDNP polarizing agent and known neuroprotective agent, on cerebral lactate metabolism were studied to understand the dissimilar metabolic trends observed compared to previous studies. The simultaneous injection of this radical with a bolus of lactate, prepolarized with the trityl radical OX063, resulted in a higher pyruvate labeling. This emphasizes that free radicals used as polarizing agents in dDNP, despite their low dose, are not biologically inert and must be carefully considered to avoid experimental bias. A successful HP MR experiment requires repeatable production of HP substrates. To this end, the custom fluid path (CFP) and the corresponding cryogenic probe were implemented on a dDNP polarizer to reduce user variability. This not only improved the consistency of both the polarization and concentration, but also enhanced the overall cryogenic and DNP performance, and facilitated the optimization of sample formulations via longitudinally detected electron spin resonance (LOD-ESR) measurements. A multi-sample dDNP probe was built to extend the application range of HP MR. Up to three samples can be polarized simultaneously while being individually monitored, even with distinct nuclei and radicals, and then sequentially dissolved. This increases the throughput of dDNP several folds and could enable the investigation of HP multi-agent theranostic approaches to gain a more comprehensive view and target multiple facets of stroke. To characterize the dynamic regional metabolic patterns in stroke, a carbon-13 cross-coil setup was constructed to provide sensitive coverage of the entire mouse brain, and a model-based dynamic multi-slice MR spectroscopic imaging sequence was implemented to achieve efficient sampling. This allowed mapping the cerebral biodistribution and metabolism of HP [1-13C] pyruvate with high spatiotemporal resolution, showing a distinct higher and faster lactate labeling in infarcted tissue compared to healthy regions.

Brain microstructural and functional MRI: developments and application to a rat model of Alzheimer's disease

Y. Diao / R. Gruetter; I. O. Jelescu (Dir.)

Magnetic resonance imaging (MRI) has been a valuable tool in investigating the pathological cascade of Alzheimer's disease (AD) and its progression, which are still open questions. Although some MRI-derived hallmarks in terms of functional connectivity and white matter degeneration have been revealed, the temporal involvement and interplay between them as well as other hallmarks such as amyloid load and neuronal density remain poorly understood. On the other hand, brain glucose hypometabolism is gradually taking center stage as a key player in the onset of AD, which had been described as a form of "type-3 diabetes". In this context, this thesis work presents a comprehensive study to characterize longitudinal changes in functional connectivity using resting-state functional MRI and microstructure using diffusion MRI, and to correlate them to glucose hypometabolism and neuronal density in a rat model of AD. This study is mainly focused on establishing an optimized image processing pipeline dedicated for rat fMRI data, optimizing a computational model of diffusion in white matter using a novel deep learning approach, and assessing the spatiotemporal relationships between biomarkers regarding to microstructure and function in the brain by using advanced statistical methods as well as state-of-the-art machine learning approaches in order to provide a comprehensive characterization of the pathological cascade and progression of neurodegeneration resulting from brain glucose metabolism disruption.

Deletion of Crtc1 leads to hippocampal neuroenergetic impairments associated with depressive-like behavior

A. Cherix; C. Poitry-Yamate; B. Lanz; O. Zanoletti; J. Grosse  et al.

Mood disorders (MD) are a major burden on society as their biology remains poorly understood, challenging both diagnosis and therapy. Among many observed biological dysfunctions, homeostatic dysregulation, such as metabolic syndrome (MeS), shows considerable comorbidity with MD. Recently, CREB-regulated transcription coactivator 1 (CRTC1), a regulator of brain metabolism, was proposed as a promising factor to understand this relationship. Searching for imaging biomarkers and associating them with pathophysiological mechanisms using preclinical models can provide significant insight into these complex psychiatric diseases and help the development of personalized healthcare. Here, we used neuroimaging technologies to show that deletion of Crtc1 in mice leads to an imaging fingerprint of hippocampal metabolic impairment related to depressive-like behavior. By identifying a deficiency in hippocampal glucose metabolism as the underlying molecular/physiological origin of the markers, we could assign an energy-boosting mood-stabilizing treatment, ebselen, which rescued behavior and neuroimaging markers. Finally, our results point toward the GABAergic system as a potential therapeutic target for behavioral dysfunctions related to metabolic disorders. This study provides new insights on Crtc1's and MeS's relationship to MD and establishes depression-related markers with clinical potential.

DOI : 10.1038/s41380-022-01791-5

Hyperpolarized (1-13C)Alaninamide Is a Multifunctional In Vivo Sensor of Aminopeptidase N Activity, pH, and CO2

A. Radaelli; D. Ortiz; A. Michelotti; M. Roche; R. Hata  et al.

Spin hyperpolarization enables real-time metabolic imaging of carbon-13-labeled substrates. While hyperpolarized L- (1-13C)alaninamide is a probe of the cell-surface tumor marker aminopeptidase-N (APN, CD13), its activity in vivo has not been described. Scanning the kidneys of rats infused with hyperpolarized alaninamide shows both conversion to [1-13C]alanine and several additional spectral peaks with distinct temporal dynamics. The (1-13C)alaninamide chemical shift is pH-sensitive, with a pKa of 7.9 at 37 degrees C, and the peaks correspond to at least three different compartments of pH 7.46 +/- 0.02 (1), 7.21 +/- 0.02 (2), and 6.58 +/- 0.05 (3). An additional peak was assigned to the carboxyamino adduct formed by reaction with dissolved CO2. Spectroscopic imaging showed nonuniform distribution, with the low-pH signal more concentrated in the inner medulla. Treatment with the diuretic acetazolamide resulted in significant pH shifts in compartment 1 to 7.38 +/- 0.03 (p = 0.0057) and compartment 3 to 6.80 +/- 0.05 (p = 0.0019). While the pH of compartment 1 correlates with blood pH, the pH of compartment 3 did not correspond to the pH of urine. In vitro experiments show that alaninamide readily enters blood cells and can detect intracellular pH. While carbamate formation depends on pH and pCO2, the carbamate-toalaninamide ratio did not correlate with either arterial blood pH or pCO2, suggesting that it may reflect variations in tissue pH and pCO2. This study demonstrates the feasibility of using hyperpolarized sensors to simultaneously image enzyme activity, pCO2, and pH in vivo.

DOI : 10.1021/acssensors.2c01203

Segmenting electroencephalography wires reduces radiofrequency shielding artifacts in simultaneous electroencephalography and functional magnetic resonance imaging at 7 T

T. P. Lê; R. Gruetter; J. Jorge; Ö. Ipek

Purpose: Simultaneous scalp electroencephalography and functional magnetic resonance imaging (EEG-fMRI) enable noninvasive assessment of brain function with high spatial and temporal resolution. However, at ultra-high field, the data quality of both modalities is degraded by mutual interactions. Here, we thoroughly investigated the radiofrequency (RF) shielding artifact of a state-of-the-art EEG-fMRI setup, at 7 T, and design a practical solution to limit this issue. Methods: Electromagnetic field simulations and MR measurements assessed the shielding effect of the EEG setup, more specifically the EEG wiring. The effectiveness of segmenting the wiring with resistors to reduce the transmit field disruption was evaluated on a wire-only EEG model and a simulation model of the EEG cap. Results: The EEG wiring was found to exert a dominant effect on the disruption of the transmit field, whose intensity varied periodically as a function of the wire length. Breaking the electrical continuity of the EEG wires into segments shorter than one quarter RF wavelength in air (25 cm at 7 T) reduced significantly the RF shielding artifacts. Simulations of the EEG cap with segmented wires indicated similar improvements for a moderate increase of the power deposition. Conclusion: We demonstrated that segmenting the EEG wiring into shorter lengths using commercially available nonmagnetic resistors is effective at reducing RF shielding artifacts in simultaneous EEG-fMRI. This prevents the formation of RF-induced standing waves, without substantial specific absorption rate (SAR) penalties, and thereby enables benefiting from the functional sensitivity boosts achievable at ultra-high field.

DOI : 10.1002/mrm.29298

Central nervous system and systemic oxidative stress interplay with inflammation in a bile duct ligation rat model of type C hepatic encephalopathy (vol 178, pg 295, 2022)

K. Pierzchala; D. Simicic; A. Sienkiewicz; D. Sessa; S. Mitrea  et al.

DOI : 10.1016/j.freeradbiomed.2022.01.016

[13C]bicarbonate labelled from hyperpolarized [1-13C]pyruvate is an in vivo marker of hepatic gluconeogenesis in fasted state

E. Can; J. A. M. Bastiaansen; D.-L. Couturier; R. Gruetter; H. A. I. Yoshihara  et al.

Hyperpolarized [1-13C]pyruvate enables direct in vivo assessment of real-time liver enzymatic activities by 13C magnetic resonance. However, the technique usually requires the injection of a highly supraphysiological dose of pyruvate. We herein demonstrate that liver metabolism can be measured in vivo with hyperpolarized [1-13C]pyruvate administered at two- to three-fold the basal plasma concentration. The flux through pyruvate dehydrogenase, assessed by 13C-labeling of bicarbonate in the fed condition, was found to be saturated or partially inhibited by supraphysiological doses of hyperpolarized [1-13C]pyruvate. The [13C]bicarbonate signal detected in the liver of fasted rats nearly vanished after treatment with a phosphoenolpyruvate carboxykinase (PEPCK) inhibitor, indicating that the signal originates from the flux through PEPCK. In addition, the normalized [13C]bicarbonate signal in fasted untreated animals is dose independent across a 10-fold range, highlighting that PEPCK and pyruvate carboxylase are not saturated and that hepatic gluconeogenesis can be directly probed in vivo with hyperpolarized [1-13C]pyruvate.

DOI : 10.1038/s42003-021-02978-2

Advanced metabolite mapping at ultra-high field using 1H-MRS, 1H-MRSI and macromolecules: applications in a rat model of type C hepatic encephalopathy

D. Simicic / R. Gruetter; C. R. Cudalbu (Dir.)

Magnetic Resonance Spectroscopy (MRS) is the only technique capable of measuring a large number of metabolites simultaneously in vivo. Ultra-high magnetic fields (UHF) combined with ultra-short echo time (TE) sequences allow the detection of high-quality 1H MR spectra and the quantification of 20 different metabolites in the brain (markers of energy metabolism, osmoregulation etc.). In vivo brain localized 1H MR spectra at short TEs contain the contribution of mobile macromolecules (MM). Reliable detection and fitting of MM are crucial for accurate quantification. Higher spectral resolution at UHF led to increased interest in using a parametrized MM spectrum and flexible spline baselines to address unpredicted spectroscopic components. In this thesis the MM spectra (from the rat brain at 9.4T) were characterized using an improved methodological approach for their post-processing, fitting and quantification. This method provided an efficient tool for parametrization of the MM spectrum into individual components and estimation of their T2app relaxation times. An extensive assessment on how the MM spectrum and spline baseline stiffness affect the metabolite and MM quantification is also reported Type C hepatic encephalopathy (HE) is a complication of chronic liver disease (CLD). Children and adults respond differently to CLD and its related toxic accumulation of molecules (i.e. ammonium (NH4+), glutamine (Gln)). Children with CLD may grow up with significant neurocognitive deficits even after liver transplantation. Despite considerable advances in understanding the pathogenesis of type C HE, the exact metabolic mechanisms and their regional variations are not fully understood. The advantages of UHF short TE 1H MRS were used herein to describe the regional distribution of metabolites in the developing and adult brain using the bile duct ligated model (BDL) of type C HE (adult and postnatal day 21 rats). Three brain regions were assessed (hippocampus, cerebellum and striatum) pointing towards cerebellum as a region with the heaviest burden of Gln and unique metabolic response. Changes in cell morphology were followed longitudinally and related to the metabolic alterations. Elevated oxidative stress is reported using electron paramagnetic resonance, together with the decreased antioxidants (1H MRS) emphasizing its important role in HE. The brain regional measurements confirmed the higher susceptibility of developing brain to the disease and the increased vulnerability of cerebellum. Finally, the beneficial effect of Cr supplementation on the neurometabolic profile is described using 1H MRS and 31P MRS in CLD pups (BDL at postnatal day 15) suggesting that an appropriate treatment may have significant public health impact. MRSI is a powerful tool to non-invasively and spatially map the brain regional distribution of metabolites in vivo. While MRSI in human brain is increasingly used, preclinical MRSI is not widely applied mainly due to the small rodent brain, long acquisition times and low signal to noise ratio. The implementation of a novel approach: free induction decay (FID) MRSI on the 14.1T preclinical scanner is described herein. This method offers a fast and robust data acquisition with high spatial resolution resulting in high quality spectroscopic maps. Finally, preliminary assessment of the effect of two noise reduction techniques (MP-PCA and TGV reconstruction) on the spectra from preclinical MRSI datasets is briefly presented.

Central nervous system and systemic oxidative stress interplay with inflammation in a bile duct ligation rat model of type C hepatic encephalopathy

K. Pierzchala; D. Simicic; A. Sienkiewicz; D. Sessa; S. Mitrea  et al.

The role and coexistence of oxidative stress (OS) and inflammation in type C hepatic encephalopathy (C HE) is a subject of intense debate. Under normal conditions the physiological levels of intracellular reactive oxygen species are controlled by the counteracting antioxidant response to maintain redox homeostasis. Our previous invivo 1H-MRS studies revealed the longitudinal impairment of the antioxidant system (ascorbate) in a bile-duct ligation (BDL) rat model of type C HE. Therefore, the aim of this work was to examine the course of central nervous system (CNS) OS and systemic OS, as well as to check for their co-existence with inflammation in the BDL rat model of type C HE. To this end, we implemented a multidisciplinary approach, including ex-vivo and in-vitro electron paramagnetic resonance spectroscopy (EPR) spin-trapping, which was combined with UV-Vis spectroscopy, and histological assessments. We hypothesized that OS and inflammation act synergistically in the pathophysiology of type C HE. Our findings point to an increased CNS- and systemic-OS and inflammation over the course of type C HE progression. In particular, an increase in the CNS OS was observed as early as 2-weeks post-BDL, while the systemic OS became significant at week 6 post-BDL. The CNS EPR measurements were further validated by a substantial accumulation of 8-Oxo-2 '-deoxyguanosine (Oxo-8-dG), a marker of oxidative DNA/RNA modifications on immunohistochemistry (IHC). Using IHC, we also detected increased synthesis of antioxidants, glutathione peroxidase 1 (GPX-1) and superoxide dismutases (i.e.Cu/ZnSOD (SOD1) and MnSOD (SOD2)), along with proinflammatory cytokine interleukin-6 (IL-6) in the brains of BDL rats. The presence of systemic inflammation was observed already at 2-weeks post-surgery. Thus, these results suggest that CNS OS is an early event in type C HE rat model, which seems to precede systemic OS. Finally, our results suggest that the increase in CNS OS is due to enhanced formation of intra- and extra-cellular ROS rather than due to reduced antioxidant capacity, and that OS in parallel with inflammation plays a significant role in type C HE.

DOI : 10.1016/j.freeradbiomed.2021.12.011

Probiotics combined with rifaximin influence the neurometabolic changes in a rat model of type C HE

E. Flatt; V. A. McLin; O. Braissant; K. Pierzchala; P. Mastromarino  et al.

Type C hepatic encephalopathy (HE) is a neuropsychiatric disease caused by chronic liver disease. Management of type C HE remains an important challenge because treatment options are limited. Both the antibiotic rifaximin and probiotics have been reported to reduce the symptoms of HE, but longitudinal studies assessing their effects on brain metabolism are lacking and the molecular mechanisms underpinning their effects are not fully understood. Therefore, we evaluated in detail the effects of these different treatments on the neurometabolic changes associated with type C HE using a multimodal approach including ultra-high field in vivo H-1 MRS. We analyzed longitudinally the effect of rifaximin alone or in combination with the probiotic Vivomixx on the brain metabolic profile in the hippocampus and cerebellum of bile duct ligated (BDL) rats, an established model of type C HE. Overall, while rifaximin alone appeared to induce no significant effect on the neurometabolic profile of BDL rats, its association with the probiotic resulted in more attenuated neurometabolic alterations in BDL rats followed longitudinally (i.e. a smaller increase in Gln and milder decrease in Glu and Cr levels). Given that both rifaximin and some probiotics are used in the treatment of HE, the implications of these findings may be clinically relevant.

DOI : 10.1038/s41598-021-97018-8

Evaluation of the whole auditory pathway using high-resolution and functional MRI at 7T parallel-transmit

S. Da Costa; J. Clement; R. Gruetter; O. Ipek

Purpose The aim of the present study is to show a MR procedure for the evaluation of simultaneous left and right auditory functions with functional MRI, and high-resolution acquisition of anatomical auditory pathway using parallel-transmit (pTx) methods at 7T.

DOI : 10.1371/journal.pone.0254378

Radical-free hyperpolarized MRI using endogenously occurring pyruvate analogues and UV-induced nonpersistent radicals

C. C. Zanella; A. Capozzi; H. A. Yoshihara; A. Radaelli; A. L. C. Mackowiak  et al.

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.

DOI : 10.1002/nbm.4584

Measuring Glycolytic Activity with Hyperpolarized [2H7, U-13C6] D-Glucose in the Naive Mouse Brain under Different Anesthetic Conditions

E. Flatt; B. Lanz; Y. Pilloud; A. Capozzi; M. H. Lerche  et al.

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

D. Wenz; R. Gruetter

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.

DOI : 10.3389/fphy.2021.675509

Redox Dysregulation, Myelination Deficit and Dysconnectivity in Schizophrenia: A Translational Study in First Episode Patients and Experimental Models

K. Q. Do; J.-H. Cabungcal; M. Cleusix; D. Dwir; M. Fournier  et al.

PIRACY: An Optimized Pipeline for Functional Connectivity Analysis in the Rat Brain

Y. Diao; T. Yin; R. Gruetter; I. Jelescu

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.

DOI : 10.3389/fnins.2021.602170

Hyperpolarized C-13-glucose magnetic resonance highlights reduced aerobic glycolysis in vivo in infiltrative glioblastoma

M. Mishkovsky; O. Gusyatiner; B. Lanz; C. Cudalbu; I. Vassallo  et al.

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

Excitatory/inhibitory neuronal metabolic balance in mouse hippocampus upon infusion of [U-C-13(6)]glucose

A. Cherix; G. Donati; B. Lizarbe; B. Lanz; C. Poitry-Yamate  et al.

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.

DOI : 10.1177/0271678X20910535

Development and applications of hyperpolarized 13C and 1H MR spectroscopy of cerebral metabolism at ultra-high field

E. I. Flatt / R. Gruetter (Dir.)

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.

Late post‐natal neurometabolic development in healthy male rats using 1 H and 31 P Magnetic Resonance Spectroscopy

V. Račkayová; D. Simicic; G. Donati; O. Braissant; R. Gruetter  et al.

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.

DOI : 10.1111/jnc.15294

The relationship between EEG and fMRI connectomes is reproducible across simultaneous EEG-fMRI studies from 1.5T to 7T

J. Wirsich; J. Jorge; G. R. Iannotti; E. A. Shamshiri; F. Grouiller  et al.

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

Methods to Enhance Nuclear Magnetic Resonance Sensitivity at High Magnetic Field

C. C. Zanella / R. Gruetter (Dir.)

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.

Mechanistic studies of DNP and applications of hyperpolarized probes to study renal physiology and metabolism

A. Radaelli / R. Gruetter; H. A. I. Yoshihara (Dir.)

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.

Brain NAD Is Associated With ATP Energy Production and Membrane Phospholipid Turnover in Humans

B. Cuenoud; O. Ipek; M. Shevlyakova; M. Beaumont; S. C. Cunnane  et al.

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.

DOI : 10.3389/fnagi.2020.609517

Contribution of macromolecules to brain H-1 MR spectra: Experts' consensus recommendations

C. Cudalbu; K. L. Behar; P. K. Bhattacharyya; W. Bogner; T. Borbath  et al.

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.

DOI : 10.1002/nbm.4393

Magnetic resonance spectroscopy in the rodent brain: Experts' consensus recommendations

B. Lanz; A. Abaei; O. Braissant; I.-Y. Choi; C. Cudalbu  et al.

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.

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

A. Radaelli; H. A. Yoshihara; H. Nonaka; S. Sando; J. H. Ardenkjaer-Larsen  et al.

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.

DOI : 10.1021/acs.jpclett.0c01473

B(0)shimming for in vivo magnetic resonance spectroscopy: Experts' consensus recommendations

C. Juchem; C. Cudalbu; R. A. de Graaf; R. Gruetter; A. Henning  et al.

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.

DOI : 10.1002/nbm.4350

Combined deletion of Glut1 and Glut3 impairs lung adenocarcinoma growth

C. Contat; P.-B. Ancey; N. Zangger; S. Sabatino; J. Pascual  et al.

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

H. Lei; R. Gruetter

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.

DOI : 10.1111/jnc.15028

The Appearance of the Warburg Effect in the Developing Avian Eye Characterized In Ovo: How Neurogenesis Can Remodel Neuroenergetics

A. Cherix; L. Brodier; C. Poitry-Yamate; J.-M. Matter; R. Gruetter

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.

DOI : 10.1167/iovs.61.5.3

Redox Dysregulation, Myelination Deficit and Dysconnectivity in Schizophrenia: A Translational Study in First Episode Patients and Experimental Models

K. Q. Do; P. S. Baumann; J.-H. Cabungcal; M. Cleusix; M. Fournier  et al.

In vivo detection of d-amino acid oxidase with hyperpolarized d-[1-C-13]alanine

A. Radaelli; R. Gruetter; H. A. I. Yoshihara

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.

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

M. Pellegrin; K. Bouzourène; J.-F. Aubert; C. Bielmann; R. Gruetter  et al.

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

Metabolic and hemodynamic changes in the activated human brain and cerebellar organisation measured by MRS/MRl at 7 Tesla

Y. Boillat / R. Gruetter (Dir.)

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.

Fat navigators based retrospective motion correction strategies for brain magnetic resonance imaging

F. Gretsch / R. Gruetter; D. Gallichan (Dir.)

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 Ì e 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.

Glutamine-to-glutamate ratio in the nucleus accumbens predicts effort-based motivated performance in humans

A. V. I. Strasser; G. Luksys; L. Xin; M. Pessiglione; R. Gruetter  et al.

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

Metabolic signature in nucleus accumbens for anti-depressant-like effects of acetyl-L-carnitine

A. Cherix; T. Larrieu; J. Grosse; J. Rodrigues; B. McEwen  et al.

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

Study of brain metabolic dysfunctions in animal models of mood disorder using magnetic resonance spectroscopy

A. T. Cherix / R. Gruetter; J.-R. Cardinaux (Dir.)

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 animalâ s 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.

Brain Regional Susceptibility to Oxidative Stress in a Rat Model of Chronic Hepatic Encephalopathy: In-Vivo 1H MRS, Ex-Vivo ESR Spectroscopy and Histology Findings

K. Pierzchala; D. Simicic; V. Rackayova; D. Sessa; A. Sienkiewicz  et al.

Glucose transporter 2 mediates the hypoglycemia-induced increase in cerebral blood flow

H. Lei; F. Preitner; G. Labouebe; R. Gruetter; B. Thorens

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.

DOI : 10.1177/0271678X18766743

Antibiotic Rifaximin for Treatment of Chronic Liver Disease-Induced HE: A Longitudinal In Vivo 1H-MRS Study of Brain Metabolism on BDL Rats

E. Flatt; O. Braissant; S. Mitrea; D. Sessa; R. Gruetter  et al.

Probiotics Combined With Rifaximin for the Treatment of Chronic Hepatic Encephalopathy: A Longitudinal In Vivo 1H-MRS Study of Brain Metabolism Using BDL Rats

E. Flatt; O. Braissant; S. Mitrea; D. Sessa; P. Mastromarino  et al.

N-Acetyl-Cysteine Supplementation Improves Functional Connectivity Within the Cingulate Cortex in Early Psychosis: A Pilot Study

E. Mullier; T. Roine; A. Griffa; L. Xin; P. S. Baumann  et al.

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.

DOI : 10.1093/ijnp/pyz022

Nutritional ketosis increases NAD plus /NADH ratio in healthy human brain: an in vivo study by P-31-MRS

L. Xin; O. Ipek; M. Beaumont; M. Shevlyakova; N. Christinat  et al.

Evolution of the neurochemical profiles in the G93A-SOD1 mouse model of amyotrophic lateral sclerosis

H. Lei; E. A. Dirren; C. Poitry-Yamate; B. Schneider; R. Gruetter  et al.

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.

DOI : 10.1177/0271678X18756499

Capturing the spatiotemporal dynamics of self-generated, task-initiated thoughts with EEG and fMRI

L. Bréchet; D. Brunet; G. Birot; R. Gruetter; C. M. Michel  et al.

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

A combined 32‐channel receive‐loops/8‐channel transmit‐dipoles coil array for whole‐brain MR imaging at 7T

J. Clément; R. Gruetter; Ö. Ipek

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.

DOI : 10.1002/mrm.27808

High-fat diet consumption alters energy metabolism in the mouse hypothalamus

B. Lizarbe; A. Cherix; J. M. N. Duarte; J.-R. Cardinaux; R. Gruetter

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.

DOI : 10.1038/s41366-018-0224-9

A human cerebral and cerebellar 8-channel transceive RF dipole coil array at 7T

J. D. Clément; R. Gruetter; Ö. Ipek

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.

DOI : 10.1002/mrm.27476

Multi-slice passband bSSFP for human and rodent fMRI at ultra-high field

O. Reynaud; A. R. da Silva; R. Gruetter; I. O. Jelescu

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.

DOI : 10.1016/j.jmr.2019.05.010

Methodological consensus on clinical proton MRS of the brain: Review and recommendations

M. Wilson; O. Andronesi; P. B. Barker; R. Bartha; A. Bizzi  et al.

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.

DOI : 10.1002/mrm.27742

Improved off‐resonance phase behavior using a phase‐inverted adiabatic half‐passage pulse for 13 C MRS in humans at 7 T

E. Serés Roig; L. Xin; D. Gallichan; V. Mlynarik; R. Gruetter

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.

DOI : 10.1002/nbm.4171

Nucleus accumbens neurochemistry in human anxiety: A 7 T 1H-MRS study

A. Strasser; L. Xin; R. Gruetter; C. Sandi

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

Alterations of Brain Energy Metabolism in Type 2 Diabetic Goto-Kakizaki Rats Measured In Vivo by (13)C Magnetic Resonance Spectroscopy

F.-M. Girault; S. Sonnay; R. Gruetter; J. M. N. Duarte

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

Investigating the variability of cardiac pulse artifacts across heartbeats in simultaneous EEG-fMRI recordings: A 7T study

J. Jorge; C. Bouloc; L. Bréchet; C. M. Michel; R. Gruetter

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

Metabolite concentration changes associated with positive and negative BOLD responses in the human visual cortex: A functional MRS study at 7 Tesla

Y. Boillat; L. Xin; W. van der Zwaag; R. Gruetter

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.

DOI : 10.1177/0271678X19831022

Engineering Parallel Transmit/Receive Radio-Frequency Coil Arrays for Human Brain MRI at 7 Tesla

J. D. Clément / R. Gruetter; Ö. Ipek (Dir.)

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.

Impact of Caffeine Consumption on Type 2 Diabetes-Induced Spatial Memory Impairment and Neurochemical Alterations in the Hippocampus

J. M. N. Duarte; C. Skoug; H. B. Silva; R. A. Carvalho; R. Gruetter  et al.

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.

DOI : 10.3389/fnins.2018.01015

Underlying mechanisms of episodic autobiographical memory and self-consciousness

L. Bréchet / R. Gruetter; C. Michel (Dir.)

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.

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-Sequencing

M. Hegi; C. Cudalbu; P. Bady; M. Lai; L. Xin  et al.

Feasibility of in vivo measurement of glucose metabolism in the mouse hypothalamus by (1) H-[(13) C] MRS at 14.1T

B. Lizarbe Serra; H. Lei; J. M. das Neves Duarte; B. Lanz; A. Cherix  et al.

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.

DOI : 10.1002/mrm.27129

Probing cardiac metabolism by hyperpolarized 13C MR using an exclusively endogenous substrate mixture and photo-induced nonpersistent radicals

J. A. M. Bastiaansen; H. A. I. Yoshihara; A. Capozzi; J. Schwitter; R. Gruetter  et al.

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.

DOI : 10.1002/mrm.27122

An Add-On Trial With N-Acetyl-Cysteine (Nac) In Early Psychosis Patients: Towards Biomarker Guided Treatment

P. Conus; M. Fournier; L. Xin; M. Cleusix; P. Baumann  et al.

Nutritional Ketosis Increases NAD+/NADH Ratio in Healthy Human Brain: An in Vivo Study by 31P-MRS

L. Xin; Ö. Ipek; M. Beaumont; M. Shevlyakova; N. Christinat  et al.

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.

DOI : 10.3389/fnut.2018.00062

Cannabis use in early psychosis is associated with reduced glutamate levels in the prefrontal cortex

S. Rigucci; L. Xin; P. Klauser; P. S. Baumann; L. Alameda  et al.

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

Ultra high magnetic field for glial contribution into brain metabolism studied by MR spectroscopy and CEST methods for molecular imaging of glycogen

E. M. C. Vinckenbosch / R. Gruetter (Dir.)

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.

Clinical Neuroimaging Using 7 T MRI: Challenges and Prospects

M. I. Vargas; P. Martelli; L. Xin; O. Ipek; F. Grouiller  et al.

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.

DOI : 10.1111/jon.12481

Increased hepatic fatty acid polyunsaturation precedes ectopic lipid deposition in the liver in adaptation to high-fat diets in mice

A. F. Soares; J. M. das Neves Duarte; R. Gruetter

DOI : 10.1007/s10334-017-0654-8

Detection of D-amino acid oxidase using hyperpolarized molecular probes

A. Radaelli; H. A. I. Yoshihara; R. Gruetter

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.

Assessing γ-glutamyl transpeptidase activity in kidney using hyperpolarized γ-Glu-[1-13C]Gly

S. F. Frank; M. Itoda; S. Sando; R. Gruetter; A. Comment  et al.

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 [3] 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.

Brain metabolism during Chronic Hepatic Encephalopathy studied by in vivo 1H and 31P MRS

V. Rackayová / R. Gruetter; C. R. Cudalbu (Dir.)

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.

Astrocytic and neuronal oxidative metabolism are coupled to the rate of glutamate-glutamine cycle in the tree shrew visual cortex

S. Sonnay; J. Poirot; N. Just; A.-C. Clerc; R. Gruetter  et al.

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

N-acetylcysteine add-on treatment leads to an improvement of fornix white matter integrity in early psychosis: a double-blind randomized placebo-controlled trial

P. Klauser; L. Xin; M. Fournier; A. Griffa; M. Cleusix  et al.

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

Probing renal pH using hyperpolarized [1-13C]alaninamide

A. Radaelli; R. Hata; S. Sando; O. Bonny; A. Comment  et al.

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.

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

M. Lai; B. Lanz; C. Poitry-Yamate; J. F. Romero; C. M. Berset  et al.

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.

DOI : 10.1177/0271678X17734101

Probing perturbed hepatic metabolism in bile-duct-ligated rats with hyperpolarized 13C pyruvate and arginine

H. A. I. Yoshihara; D. Firsov; C. R. Cudalbu; R. Gruetter

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.

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

M. Lai; I. Vassallo; B. Lanz; C. Poitry-Yamate; M.-F. Hamou  et al.

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.

DOI : 10.1002/ijc.31299

Mapping and characterization of positive and negative BOLD responses to visual stimulation in multiple brain regions at 7T

J. Jorge; p. figueiredo; R. Gruetter; W. Van der Zwaag

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.

DOI : 10.1002/hbm.24012

In Vivo Heteronuclear Magnetic Resonance Spectroscopy

B. Lizarbe; A. Cherix; R. Gruetter

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.

DOI : 10.1007/978-1-4939-7531-0_11.

Redox dysregulation in schizophrenia pathophysiology: add-on trial with N-acetylcysteine (NAC) in early psychosis patients

M. Fournier; P. Conus; L. Seidman; L. Xin; M. Cleusix  et al.

Altered glycogen metabolism in the brain of insulin-resistant Goto-Kakizaki rats: a 13C magnetic resonance spectroscopy study in V

J. D. N. Duarte; A. F. Soares; S. Nussbaum; R. Gruetter

Defining mitochondrial biomarkers and function using magnetic resonance spectroscopy at 14.1 Tesla in a mouse model of mood disorders

A. Cherix; G. Donati; B. Lizarbe; H. Lei; J. -R. Cardinaux  et al.

Investigating mitochondrial biomarkers and function using MRS at 14.1 Tesla in a mouse model of mood disorders

A. Cherix; G. Donati; B. Lizarbe; H. Lei; -R. Cardinaux  et al.

In vivo cerebral metabolism of glioblastoma xenografts assessed with ¹H MRS, ¹³C MRS and ¹⁸F-FDG PET

M. Lai / R. Gruetter (Dir.)

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.

Energy metabolism in the rat cortex under thiopental anaesthesia measured

S. Sonnay; J. M. N. Duarte; N. Just; R. Gruetter

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.

DOI : 10.1002/jnr.24032

How Energy Metabolism Supports Cerebral Function: Insights from 13C Magnetic Resonance Studies In vivo

S. Sonnay; R. Gruetter; J. M. N. Duarte

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.

DOI : 10.3389/fnins.2017.00288

N-Acetyl-Cysteine In A Doubleblind Randomized Placebo-Controlled Trial: Toward Biomarker-Guided Treatment In Early Psychosis

K. Do; L. J. Seidman; M. Fournier; L. Xin; M. Cleusix  et al.

Study of cortical energy metabolism during sensory stimulation-induced brain activity by ¹³C magnetic resonance spectroscopy in vivo

S. C. Sonnay / R. Gruetter (Dir.)

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.

Influence of physiological noise on accelerated 2D and 3D resting state functional MRI data at 7 T

O. Reynaud; J. Jorge; R. Gruetter; J. P. Marques; W. van der Zwaag

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.

DOI : 10.1002/mrm.26823

Hyperpolarization of 2-keto[1-13C]isocaproate for in vivo studies with photo-induced radicals

F. Steffen; H. A. I. Yoshihara; M. Mishkovsky; A. Comment; R. Gruetter

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 dynamic

In vivo detection of hypothalamic glucose metabolism in HFD and regular fed mice

B. Lizarbe; H. Lei; A. Cherix; R. Gruetter

Coupling of the glutamate-glutamine cycle rate with both glial and neuronal oxidative metabolism in the visual cortex of the Tupaia belangeri

S. Sonnay; J. Poirot; N. Just; A. -C. Clerc; R. Gruetter  et al.

Sexual dimorphism in hepatic lipids is associated with the evolution of metabolic status in mice

A. F. Soares; J. Paz-Montoya; H. Lei; M. Moniatte; R. Gruetter

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.

DOI : 10.1002/nbm.3761

Glycogen Supercompensation in the Rat Brain After Acute Hypoglycemia is Independent of Glucose Levels During Recovery

J. M. N. Duarte; F. D. Morgenthaler; R. Gruetter

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

Rates oxidative metabolism in astrocytes and neurons are coupled to the glutamate-glutamine cycle in the tree shrew visual cortex

S. Sonnay; J. Poirot; N. Just; A. -C. Clerc; R. Gruetter  et al.

Prospective head motion correction using FID-guided on-demand image navigators

M. Waszak; P. Falkovskiy; T. Hilbert; G. Bonnier; B. Maréchal  et al.

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.

DOI : 10.1002/mrm.26364

Technical and experimental features of Magnetic Resonance Spectroscopy of brain glycogen metabolism

A. F. Soares; R. Gruetter; H. Lei

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

Diffusion-weighted MRS of acetate in the rat brain

M. Dehghani; N. Kunz; B. Lanz; H. A. I. Yoshihara; R. Gruetter

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.

DOI : 10.1002/nbm.3768

Cannabis use decreases prefrontal glutamate levels in early psychosis

S. Rigucci; L. Xin; P. Klauser; P. S. Baumann; L. Alameda  et al.

Metabolite concentration changes during increase of the BOLD signal in the human visual cortex: a functional magnetic resonance spectroscopy study at 7T

Y. Boillat; L. Xin; W. Van Der Zwaag; R. Gruetter

Hierarchical status predicts behavioral vulnerability and nucleus accumbens metabolic profile following chronic social defeat stress.

T. Larrieu; A. Cherix; A. Duque; J. Rodrigues; H. Lei  et al.

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

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

A. Corcoba; R. Gruetter; K. Q. Do; J. M. N. Duarte

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.

DOI : 10.1111/jnc.14116

Progress towards in vivo brain (13)C-MRS in mice: Metabolic flux analysis in small tissue volumes

M. Lai; R. Gruetter; B. Lanz

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

Comparison diffusion behavior of metabolites in brains of congenital portal systemic shunt and healthy mice in vivo at 14.1 t

M. Dehghani; N. Kunz; R. Gruetter; H. Lei

Glucose and glycogen metabolism in the brain of insulin resistant Goto-Kakizaki rats

A. F. Soares; S. S. Nussbaum; R. Gruetter; J. M. N. Duarte

Studying cyto and myeloarchitecture of the human cortex at ultra-high field with quantitative imaging: R1, R⁎2 and susceptibility

J. P. Marques; D. Khabipova; R. Gruetter

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

N-acetyl-cysteine in a double-blind randomized placebo-controlled trial: Towards biomarker guided treatment in early psychosis

P. Conus; M. Fournier; L. Xin; P. Baumann; C. Ferrari  et al.

Genetic Polymorphism Associated Prefrontal Glutathione and Its Coupling With Brain Glutamate and Peripheral Redox Status in Early Psychosis

L. Xin; R. Mekle; M. Fournier; P. S. Baumann; C. Ferrari  et al.

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

J. P. Forjaco Jorge / R. Gruetter; P. Figueiredo (Dir.)

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.

Proton diffusion spectroscopy and modeling of brain metabolism at 14.1T

M. Dehghani Moghadam / R. Gruetter (Dir.)

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 Krebâ s 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.

Refined Analysis of Brain Energy Metabolism Using In Vivo Dynamic Enrichment of 13C Multiplets

M. Dehghani M; B. Lanz; J. M. N. Duarte; N. Kunz; R. Gruetter

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

Quantitative Susceptibility Mapping in the Human Brain

D. Khabipova / R. Gruetter; J. P. Rebelo Ferreira Marques (Dir.)

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.

Glutathione deficit affects the integrity and function of the fimbria/fornix and anterior commissure in mice: relevance for schizophrenia

A. Corcoba; P. Steullet; J. M. N. Duarte; Y. Van de Looij; A. Monin  et al.

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.

DOI : 10.1093/ijnp/pyv110

Three-dimensional echo planar imaging with controlled aliasing: A sequence for high temporal resolution functional MRI

M. Narsude; D. Gallichan; W. Van Der Zwaag; R. Gruetter; J. P. Marques

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.

DOI : 10.1002/mrm.25835

Simultaneous and interleaved acquisition of NMR signals from different nuclei with a clinical MRI scanner

M. Meyerspeer; A. W. Magill; A. Kuehne; R. Gruetter; E. Moser  et al.

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.

DOI : 10.1002/mrm.26056

Hyperpolarized 6Li as a probe for hemoglobin oxygenation level

R. Balzan; M. Mishkovsky; Y. Simonenko; R. B. van Heeswijk; R. Gruetter  et al.

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.

DOI : 10.1002/cmmi.1656

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

S. Sonnay; J. M. Duarte; N. Just; R. Gruetter

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.

DOI : 10.1177/0271678X16629482

3D T 2-weighted imaging at 7T using dynamic kT-points on single-transmit MRI systems

F. Eggenschwiler; K. R. O'Brien; D. Gallichan; R. Gruetter; J. P. Marques

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.

DOI : 10.1007/s10334-016-0545-4

Early detection of human glioma sphere xenografts in mouse brain using diffusion MRI at 14.1 T

P. Porcari; M. E. Hegi; H. Lei; -F. Hamou; I. Vassallo  et al.

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.

DOI : 10.1002/nbm.3610

Motion Correction in Magnetic Resonance Imaging Using the Signal of Free-Induction-Decay

M. V. Waszak / R. Gruetter; G. Krüger (Dir.)

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.

Quantitative activity-induced manganese-dependent MRI for characterizing cortical layers in the primary somatosensory cortex of the rat

M. Auffret; I. Samim; M. Lepore; R. Gruetter; N. Just

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.

DOI : 10.1007/s00429-014-0933-3

Retrospective correction of involuntary microscopic head movement using highly accelerated fat image navigators (3D FatNavs) at 7T

D. Gallichan; J. P. Marques; R. Gruetter

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.

DOI : 10.1002/mrm.25670

N-Acetyl-Cysteine in a double-blind randomized placebo-controlled trial: Towards biomarker guided treatment in early psychosis

P. Conus; M. Fournier; L. Xin; P. S. Baumann; L. Alameda  et al.

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

J. Bastiaansen; T. Cheng; H. Lei; R. Gruetter; A. Comment

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.

DOI : 10.1016/j.yjmcc.2015.08.012

Stroking or Buzzing? A Comparison of Somatosensory Touch Stimuli Using 7 Tesla fMRI

W. van der Zwaag; R. Gruetter; R. Martuzzi

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

Physiological noise in human cerebellar fMRI

W. Van Der Zwaag; J. Jorge; D. Butticaz; R. Gruetter

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.

DOI : 10.1007/s10334-015-0483-6

Brain energy metabolism measured by 13C magnetic resonance spectroscopy in vivo upon infusion of [3-13C]lactate

J. M. Duarte; F.-M. Girault; R. Gruetter

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.

DOI : 10.1002/jnr.23531

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

A. F. Soares; H. Lei; R. Gruetter

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.

DOI : 10.1002/nbm.3345

Metabolic flux analysis of hepatic mitochondrial oxidation of hyperpolarized [1-13C] and [2-13C] pyruvate in vivo

E. Can; J. Bastiaansen; H. A. I. Yoshihara; R. Gruetter; A. Comment

Towards high-quality simultaneous EEG-fMRI at 7T: Detection and reduction of EEG artifacts due to head motion

J. Jorge; F. Grouiller; R. Gruetter; W. Van Der Zwaag; P. Figueiredo

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

B1+-mapping and B1+ inhomogeneity correction at high field

F. Eggenschwiler / R. Gruetter (Dir.)

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.

Fast low-specific absorption rate B0-mapping along projections at high field using two-dimensional radiofrequency pulses

O. Reynaud; D. Gallichan; B. Schaller; R. Gruetter

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.

DOI : 10.1002/mrm.25217

Correcting surface coil excitation inhomogeneities in single-shot SPEN MRI

R. Schmidt; M. Mishkovsky; J.-N. Hyacinthe; N. Kunz; R. Gruetter  et al.

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.

DOI : 10.1016/j.jmr.2015.08.018

A Modulated Closed Form solution for Quantitative Susceptibility Mapping - A thorough evaluation and comparison to iterative methods based on edge prior knowledge

D. Khabipova; Y. Wiaux; R. Gruetter; J. P. Marques

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

Single acquisition electrical property mapping based on relative coil sensitivities: A proof-of-concept demonstration

J. P. Marques; D. K. Sodickson; O. Ipek; C. M. Collins; R. Gruetter

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.

DOI : 10.1002/mrm.25399

A double-quadrature radiofrequency coil design for proton-decoupled carbon-13 magnetic resonance spectroscopy in humans at 7T

E. Serés Roig; A. W. Magill; G. Donati; M. Meyerspeer; L. Xin  et al.

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.

DOI : 10.1002/mrm.25171

In Vivo Longitudinal (1)H MRS Study of Transgenic Mouse Models of Prion Disease in the Hippocampus and Cerebellum at 14.1 T

C. Cudalbu; M. Craveiro; V. Mlynárik; J. Bremer; A. Aguzzi  et al.

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

Improved surface coil design and pulse sequence development for in vivo 13C MR spectroscopy of humans at 7T

E. Serés Roig / R. Gruetter (Dir.)

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.

Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients

A. Monin; P. Baumann; A. Griffa; L. Xin; R. Mekle  et al.

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

Fasting-induced changes of hepatic lipid and carbohydrate stores in the absence of GLUT2

A. F. Soares; H. Lei; B. Thorens; R. Gruetter

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

S. Sonnay; N. Just; J. M. N. Duarte; R. Gruetter

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.

DOI : 10.1002/nbm.3263

Energy metabolism in the rat cortex under deep thiopental anesthesia measured in vivo by 13C MRS at 14.1 T

S. Sonnay; N. Just; R. Gruetter; J. M. N. Duarte

Distinct contributions of Brodmann areas 1 and 2 to body ownership

R. Martuzzi; W. Van Der Zwaag; S. Dieguez; A. Serino; R. Gruetter  et al.

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.

DOI : 10.1093/scan/nsv031

Simultaneous EEG–fMRI at ultra-high field: Artifact prevention and safety assessment

J. Jorge; F. Grouiller; Ö. Ipek; R. Stoermer; C. M. Michel  et al.

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

GDH-Dependent Glutamate Oxidation in the Brain Dictates Peripheral Energy Substrate Distribution

M. Karaca; F. Frigerio; S. Migrenne; J. Martin-Levilain; D. Skytt  et al.

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 model

H. Lei; E. Dirren; B. Schneider; S. Aebischer; R. Gruetter

Radical-free mixture of co-polarized 13C metabolites for probing separate biochemical pathways in vivo by hyperpolarized 13C MR

J. Bastiaansen; H. A. I. Yoshihara; A. Capozzi; J. Schwitter; M. Merritt  et al.

Parallel imaging with phase scrambling

M. Zaitsev; G. Schultz; J. Hennig; R. Gruetter; D. Gallichan

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.

DOI : 10.1002/mrm.25252

Assessment of metabolic fluxes in the mouse brain in vivo using (1)H-[(13)C] NMR spectroscopy at 14.1 Tesla

L. Xin; B. Lanz; H. Lei; R. Gruetter

(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.

DOI : 10.1038/jcbfm.2014.251

Evidence From Imaging Studies For Oxidative Stress Mechanisms In First Episode Schizophrenia

K. Q. Do; L. Alameda; P. S. Baumann; J. H. Cabungeal; A. Corcoba  et al.

Impact of insulin resistance on memory performance, brain morphology and neurochemical profiles of the cortex and hippocampus

J. M. N. Duarte; R. Gruetter

Experimental peripheral arterial disease: new insights into muscle glucose uptake, macrophage, and T-cell polarization during early and late stages

M. Pellegrin; K. Bouzourène; C. Poitry-Yamate; V. Mlynarik; F. Feihl  et al.

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

In vivo brain macromolecule signals in healthy and glioblastoma mouse models: 1H magnetic resonance spectroscopy, post-processing and metabolite quantification at 14.1 T

M. Craveiro; V. Clément-Schatlo; D. Marino; R. Gruetter; C. Cudalbu

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.

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

G. A. Lodygensky; N. Kunz; E. Perroud; E. Somm; V. Mlynarik  et al.

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

Impaired White Matter Integrity in Fornix and Anterior Commissure in a Schizophrenia Mouse Model of Redox Dysregulation

A. Corcoba; P. Steullet; J. M. N. Duarte; Y. Van De Looij; R. Gruetter  et al.

Longitudinal neurochemical modifications in the aging mouse brain measured in vivo by 1H magnetic resonance spectroscopy

J. M. N. Duarte; K. Q. Do; R. Gruetter

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.

DOI : 10.1016/j.neurobiolaging.2014.01.135

Improving T2 -weighted imaging at high field through the use of kT -points

F. Eggenschwiler; K. R. O'Brien; R. Gruetter; J. P. Marques

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.

DOI : 10.1002/mrm.24805

Genetic Association with Prefrontal Glutathione Deficit: A 3T 1H MRS Study in Early Psychosis

L. Xin; R. Mekle; C. Ferrari; P. S. Baumann; L. Alameda  et al.

High Temporal Resolution Functional Magnetic Resonance Imaging at 7 Tesla

M. Narsude / R. Gruetter (Dir.)

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.

Protective effects of maternal nutritional supplementation with lactoferrin on growth and brain metabolism

E. Somm; P. Larvaron; Y. Van De Looij; A. Toulotte; A. Chatagner  et al.

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

Impact of hepatic lipid accumulation and composition on glucose tolerance and insulin sensitivity: a longitudinal study in male and female mice

A. F. Soares; H. Lei; R. Gruetter

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.

Purely endogenous hyperpolarized [1-13C]Pyruvate solutions for metabolic study in glioblastoma rat models

M. Mishkovsky; E. Can; T. Eichhorn; D. Mario; I. Radovanovic  et al.

1H MRS to investigate the hepatic profile of GLUT2-/- mice

A. F. Soares; H. Lei; F. Preitner; B. Thorens; R. Gruetter

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.

Phase-based manganese enhanced MRI, a new methodology to enhance brain cytoarchitectural contrast and study manganese uptake

R. Maddage; J. P. Marques; R. Gruetter

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.

DOI : 10.1002/mrm.25037

Hyperpolarized 13C lactate as a substrate for in vivo metabolic studies in skeletal muscle

J. Bastiaansen; H. A. I. Yoshihara; Y. Takado; R. Gruetter; A. Comment

Are glutamate and lactate increases ubiquitous to physiological activation? A 1H functional MR spectroscopy study during motor activation in human brain at 7Tesla

B. Schaller; L. Xin; K. O‘Brien; A. Magill; R. Gruetter

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

Is the macromolecule signal tissue-specific in healthy human brain? A 1H MRS study at 7 tesla in the occipital lobe

B. Schaller; L. Xin; R. Gruetter

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.

DOI : 10.1002/mrm.24995

Neurochemical profile differentiation of glioma induced by cancer stem cells expressing WIF1: a 1H-MRS longitudinal study at 14.1T

M. Lai; C. R. Cudalbu; B. Lanz; I. Vassallo; M.-F. Hamou  et al.