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Magnetic resonance methods to study the brain in vivo

Méthodes de résonance magnétique in vivo pour l'étude du cerveau

Group leader : Julien Valette​

Published on 17 March 2021
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 Julien Valette

​Evaluation of cellular metabolism and structure in vivo

Neurodegenerative diseases are largely associated with alterations of cellular metabolism and structure, which may precede neuron death. The magnetic resonance methodology team is developing original methods to non-invasively assess cellular metabolism and structure, in particular in animal models developed within the research unit UMR 9199, using the 7 T and 11.7 T MRI machines in MIRCen. We pursue two ultimate goals: to propose new biomarkers of neurodegenerative diseases, and to better understand physiopathological processes at stake in those diseases.

 
Figure 1: Quantification of brain metabolites in a volume of the primate brain in vivo at 7 T


Beyond the sole determination of brain metabolite concentrations by proton spectroscopy (Figure 1), our group develops imaging methods based on CEST effect ("Chemical Exchange Saturation Transfer", Figure 2), in order to map with a good spatial resolution the distribution of some endogenous metabolite such as glutamate (which is involved in both energy metabolism and neurotransmission).


Figure 2: Decrease of glutamate concentration observed by CEST imaging in a mouse model of Huntington's disease, 
as measured on the 11.7 T scanner.



The team is strongly involved in the development of X-nuclei spectroscopy to measure of some important energy metabolism fluxes: carbon-13 (13C) spectroscopy to determine the TCA cycle (VTCA); oxygen-17 (17O) spectroscopy and imaging (Figure 3) to assess the rate of cellular respiration (CMRO2), which is itself coupled to TCA cycle; and phosphorus-31 (31P) spectroscopy to measure the ATP synthesis rate by oxidative phosphorylation (VATP). 

cmro.png

Figure 3: CMRO2 impairment in a mouse model of amyloidosis (APPswe/PS1dE9). a) Anatomical image1H and b) zero echo time (ZTE) 17O images are acquired at 11.7 T. Acquiring a series of 17O-ZTE images before, during, and after inhalation of 17O-labeled oxygen gas (70%) allows the detection of metabolically produced H217O. d) H217O signal time courses in APPswe/PS1dE9 (n=4, orange) and WT mice (n=4, blue) (with SD). (e) Quantification of CMRO2 shows a slower oxygen consumption rate in the APPswe/PS1dE9 mice than in WT (mean±SD).

In parallel, one of our current project deals with the use of CEST imaging of glucose to map cerebral metabolic rate of glucose (CMRglc). An originality of our team is that we combine these different techniques to get an integrated picture of energy metabolism (Figure 4).



Figure 4 Metabolic fluxes of mitochondrial energy synthesis, measured by our group in the primate brain. 
The fluxes are in μmol/g/min. Adapted from [Chaumeil et al., PNAS 2009].​
 

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We are also looking at the possibility of evaluating the organization of the intracellular medium in an indirect way, by measuring via original diffusion-weighted spectroscopy techniques how this organization constrains the displacement of metabolites. In particular, our group has explored the diffusion of brain metabolites over unprecedented time scales, making it possible to better characterize metabolite compartmentation and the parameters governing metabolite motion. We collaborate with the group of Itamar Ronen at the University of Leiden (the Netherlands) on this topic. We are also developing new diffusion modeling strategies (in collaboration with Marco Palombo at University College London) to extract quantitative information about the cellular structure from experimental diffusion data. Notably, we have shown that it was possible to differentiate neuronal from astrocytic structure, by studying diffusion of metabolites predominantly in neurons or in astrocytes (Figure 5). We are now investigating the possibility to use diffusion-weighted spectroscopy to assess cerebral lactate distribution between the different compartments (neurons, astrocytes, extracellular space…), which is related to the lactate shuttle. These thematics have been funded by two grants from the European Research Council ("INCELL" and "LactaDiff" projects).


Figure 5: The study of the temporal dependency of metabolite diffusion coefficient at ultra-long diffusion times allows characterizing long-range cellular structure. By looking at metabolites mostly in astrocytes (e.g. myo-inositol) or in neurons (e.g. NAA), it is even possible to differentiate astrocytic from neuronal structure. Taken from [Palombo et al., PNAS 2016]).


Group members

  • Julien Valette (CEA researcher): team leader, and leading the diffusion-weighted spectroscopy thematic
  • Céline Baligand (CEA researcher): leading the X-nuclei thematic
  • Julien Flament (INSERM research officer): leading the CEST thematic
  • Eloïse Mougel (post-doctoral fellow): diffusion-weighted spectroscopy sequences
  • Rodrigo Lerchundi (post-doctoral fellow): FRET imaging of lactate, enzyme-electrodes
  • Amélie Tourais (PhD student): 17O MRI
  • Sophie Malaquin (PhD student): diffusion-weighted spectroscopy
  • Yohann Mathieu-Daudé (PhD student): CEST imaging of glucose
  • Jean-Baptiste Pérot (PhD student): CEST imaging of glutamate
  • Mélissa Vincent (PhD student): diffusion-weighted spectroscopy


Past group members

  • Jérémy Pépin (PhD student): CEST imaging of glutamate
  • Khieu Van Nguyen (post-doctoral fellow): diffusion modeling
  • Edwin Hernandez-Garzon (post-doctoral fellow): confocal microscopy, cellular
  • Clémence Ligneul (PhD student): diffusion-weighted spectroscopy
  • Marco Palombo (post-doctoral fellow): diffusion modeling
  • Brice Tiret (PhD student): X-nuclei spectroscopy
  • Chloé Najac (PhD student): X-nuclei spectroscopy, diffusion-weighted spectroscopy
  • Charlotte Marchadour (PhD student): X-nuclei spectroscopy, diffusion-weighted spectroscopy


Collaborations

  • University of Bordeaux / RMSB (A.-K. Bouzier-Sore)
  • University College London (M. Palombo)
  • University of Minnesota (P.-G. Henry, M. Marjanska)
  • Leiden University (I. Ronen)
  • EPFL (M. Dehghani, N. Kunz, R. Gruetter)
  • Brain and Spine Institute (F. Branzoli, S. Lehéricy)


Major grants

  • ERC: LactaDiff project (2019-2024), INCELL project (2013-2018)

  • ANR: nrjCEST project (2018-2021); HDeNERGY project (2015-2019)


Recent publications


Complementarity of gluCEST and 1H-MRS for the study of mouse models of Huntington's disease.
J.Pépin, L.de Longprez, F.Trovero, E.Brouillet, J.Valette, J.Flament  
NMR Biomed.2020


Revisiting double diffusion encoding MRS in the mouse brain at 11.7T: Which microstructural features are we sensitive to ?
M.Vincent, M.Palombo, J.Valette 
Diffusion-weighted magnetic resonance spectroscopy enables cell-specific monitoring of astrocyte reactivity in vivo.
C.Ligneul, M.Palombo, E.Hernández-Garzón, M.A.Carrillo-de Sauvage, J.Flament, P.Hantraye, E.Brouillet, G.Bonvento, C.Escartin, J.Valette

Efficient GPU-based Monte-Carlo simulation of diffusion in real astrocytes reconstructed from confocal microscopy
K.V.Nguyen, E.Hernández-Garzón, J.Valette


In Vivo Multidimensional Brain Imaging in Huntington's Disease Animal Models
J.Flament, P.Hantraye, J.Valette



Brain Metabolite Diffusion from Ultra-Short to Ultra-Long Time Scales: What Do We Learn, Where Should We Go?
J.Valette, C.Ligneul, C.Marchadour, C.Najac, M.Palombo 

Feedback control of microbubble cavitation for ultrasound-mediated blood-brain barrier disruption in non-human primates under magnetic resonance guidance
H.A.Kamimura, J.Flament, J.Valette, A.Cafarelli, R.Aron Badin, P.Hantraye, B.Larrat

Insights into brain microstructure from in vivo DW-MRS 
M.Palombo, N.Shemesh, I.Ronen, J.Valette 

Can we detect the effect of spines and leaflets on the diffusion of brain intracellular metabolites?
M.Palombo, C.Ligneul, E.Hernandez-Garzon, J.Valette.
Neuroimage. 2017.

Subarachnoid Hemorrhage Severely Impairs Brain Parenchymal Cerebrospinal Fluid Circulation in Nonhuman Primate
Goulay R., Flament J., Gauberti M., Naveau M., Pasquet N., Gakuba C., Emery E., Hantraye P., Vivien D., Aron-Badin R., Gaberel T.
Stroke 2017.

Primatologist: a modular segmentation pipeline for Macaque brain morphometry
Balbastre Y., Rivière D., Souedet N., Fischer C., Hérard A-S., Williams S., Vandenberghe M. E., Flament J., Aron-Badin R., Hantraye P., Mangin J-F., Delzescaux T.
NeuroImage 2017.

Using 31P-MRI of hydroxyapatite for bone attenuation correction in PET-MRI: proof of concept in the rodent brain
V.Lebon, S.Jan, Y.Fontyn, B.Tiret, G.Pottier, E.Jaumain, J.Valette.
EJNMMI Phys. 2017 Dec;4(1):16.

Probing metabolite diffusion at ultra-short time scales in the mouse brain using optimized oscillating gradients and "short" echo time diffusion-weighted MR spectroscopy
C.Ligneul, J.Valette.
NMR in Biomedicine 2017 Jan;30(1)

Modeling diffusion of intracellular metabolites in the mouse brain up to very high diffusion‐weighting: Diffusion in long fibers (almost) accounts for non‐monoexponential attenuation
M.Palombo, C.Ligneul, J.Valette.
Magnetic resonance in medicine 2016.

Imaging and spectroscopic approaches to probe brain energy metabolism dysregulation in neurodegenerative diseases
G.Bonvento, J.Valette, J.Flament, F.Mochel, E.Brouillet.
J Cereb Blood Flow Metab. 2017 Jun;37(6)

Energy defects in Huntington's disease: Why "in vivo" evidence matters
G.Liot, J.Valette, J.Pépin, J.Flament, E.Brouillet.
Biochem Biophys Res Commun. 2017 Feb 19;483(4) Review.

Experimental strategies for in vivo 13C NMR spectroscopy
J.Valette, B.Tiret, F.Boumezbeur.
Analytical Biochemistry 2017 Jul 15;529:216-228

Evidence for a "metabolically inactive" inorganic phosphate pool in adenosine triphosphate synthase reaction using localized 31P saturation transfer magnetic resonance spectroscopy in the rat brain at 11.7 T
B.Tiret, E.Brouillet, J.Valette.
J Cereb Blood Flow Metab. 2016 Jun 28

In vivo imaging of brain glutamate defects in a knock-in mouse model of Huntington's disease
J.Pépin, L.Francelle, M.A.Carrillo-de Sauvage, L.de Longprez, P.Gipchtein, K.Cambon, J.Valette, E.Brouillet, J.Flament.
Neuroimage. 2016 Jun 16;139:53-64.

New paradigm to assess brain cell morphology by diffusion-weighted MR spectroscopy in vivo
M.Palombo, C.Ligneul, C.Najac, J.Le Douce, J.Flament, C.Escartin, P.Hantraye, E.Brouillet, G.Bonvento, J.Valette.
Proc Natl Acad Sci U S A. 2016 Jun 14;113(24):6671-6.

Metabolite diffusion up to very high b in the mouse brain in vivo: Revisiting the potential correlation between relaxation and diffusion properties
C.Ligneul, M.Palombo, J.Valette.
Magn Reson Med. 2016 Mar 28. doi: 10.1002/mrm.26217

Diffusion-weighted magnetic resonance spectroscopy
I.Ronen, J.Valette.
eMagRes 2015;4:733–750.

Metabolic Modeling of Dynamic (13)C NMR Isotopomer Data in the Brain In Vivo: Fast Screening of Metabolic Models Using Automated Generation of Differential Equations
B.Tiret B, A.A.Shestov, J.Valette, P.G.Henry.
Neurochem Res. 2015 Dec;40(12):2482-92.

Brain intracellular metabolites are freely diffusing along cell fibers in grey and white matter, as measured by diffusion-weighted MR spectroscopy in the human brain at 7 T
C.Najac, F. Branzoli, I. Ronen, J.Valette. 
Brain Struct Funct. 2014 (doi : 10.1007/s00429-014-0968-5).

Intracellular metabolites in the primate brain are primarily localized in long fibers rather than in cell bodies, as shown by diffusion weighted magnetic resonance spectroscopy
C.Najac, C.Marchadour, M.Guillermier, D.Houitte, V.Slavov, E.Brouillet, P.Hantraye, V.Lebon, J.Valette. 
NeuroImage 2014 ; 90:374-380.

13C NMR spectroscopy applications to brain energy metabolism
T.B.Rodrigues, J.Valette, A.-K.Bouzier-Sore. 
Front. Neuroenergetics 2013 Dec 9 ; 5:9. Review.

Anomalous diffusion of brain metabolites evidenced by diffusion-weighted magnetic resonance spectroscopy in vivo
C.Marchadour, E.Brouillet, P.Hantraye, V.Lebon, J.Valette. 
J. Cereb. Blood Flow Metab. 2012 ; 32(12):2153-2160.

Metabolic modeling of brain 13C NMR multiplet data: concepts and simulations with a two-compartment neuronal-glial model
A.A.Shestov, J.Valette, D.K.Deelchand, K.Ugurbil, P.-G.Henry. 
Neurochem. Res. 2012 ; 37(11):2388-2401.

pH as a biomarker of neurodegeneration in Huntington's disease: a translational rodent-human MRS study
M.M.Chaumeil, J.Valette, C.Baligand, E.Brouillet, P.Hantraye, G.Bloch, V.Gaura, A.Rialland, P.Krystkowiak, C.Verny, P.Damier, P.Remy, A.-C.Bachoud-Levi, P.Carlier, V.Lebon. 
J Cereb Blood Flow Metab. 2012 ; 32(5):771-779.

A new sequence for single-shot diffusion-weighted NMR spectroscopy by the trace of the diffusion tensor
J.Valette, C.Giraudeau, C.Marchadour, B.Djemai, F.Geffroy, M.A.Ghaly, D.Le Bihan, P.Hantraye, V.Lebon, F.Lethimonnier. 
Magn Reson Med. 2012 ; 68(6):1705-1712

About the origins of NMR diffusion-weighting induced by frequency-swept pulses
J.Valette, F.Lethimonnier, V.Lebon. 
Magn. Reson. 2010; 205(2):255-259.

Simplified 13C metabolic modeling for simplified measurements of cerebral TCA cycle rate in vivo
J.Valette, F.Boumezbeur, P.Hantraye, V.Lebon.
Magn. Reson. Med. 2009 ; 62(6):1641-1645.

Multimodal neuroimaging provides a highly consistent picture of energy metabolism, validating 31P MRS for measuring brain ATP synthesis
M.M.Chaumeil, J.Valette, M.Guillermier, E.Brouillet, F.Boumezbeur, A.S.Herard, G.Bloch, P.Hantraye, V.Lebon. 
Proc. Natl. Acad. Sci. USA 2009 ; 106(10):3988–3993.