You are here : Home > Research Centers and Units > MIRCen > The Neurodegenerative Diseases ... > Magnetic resonance methods to study the brain in vivo

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 25 March 2020
​  

 

e-mail

 Julien Valette

​Evaluation of cellular metabolism and stucture in vivo

It is becoming increasingly clear that neurodegenerative diseases are associated with alterations of cellular metabolism and structure, which may precede neuron death. The main goal of the magnetic resonance spectroscopy team is to develop original methods for the non-invasive evaluation of cellular metabolism or structure, in particular in animal models developed within the UMR 9199, using the 7 T and 11.7 T MRI machines in MIRCen.

 
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 group is significantly involved in the development of X-nuclei spectroscopy for the measurement of some important energy metabolism fluxes: carbon-13 (13C) spectroscopy to determine the Krebs cycle (TCA cycle), phosphorus-31 (31P) spectroscopy to measure the ATP synthesis rate by oxidative phosphorylation (as well as intracellular pH) and, more recently, oxygen-17 (17O) spectroscopy to assess the rate of cellular respiration. We collaborate with the group of P.-G. Henry at the University of Minnesota (USA) on aspects related to acquisition and metabolic modeling for 13C spectroscopy. An originality of our group is that we combine different techniques to get an integrated picture of energy metabolism (Figure 3). Incidentally, one of our main projects involves evaluating the efficacy of ATP synthesis by mitochondria in Huntington's disease, in particular in a rodent model, through a combination of these approaches (ANR project "HDeNERGY").​



Figure 3: 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].​
 

​​
We are also investigating 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 to extract quantitative information about the cellular structure from experimental diffusion data. In particular, 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 4). This research is funded by the European Research Council (ERC project "INCELL").


Figure 4 : 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]).


Members of the laboratory associated with these projects

  • Julien Flament (INSERM research officer): leading the CEST thematic
  • Khieu Van Nguyen (post-doctoral fellow): modeling molecular diffusion in vivo
  • Mélissa Vincent (PhD student): measurement of brain metabolite diffusion
  • Edwin Hernandez-Garzon (post-doctoral fellow): confocal microscopy, cellular morphometry
  • Jérémy Pépin (PhD student): CEST imaging of endogenous metabolites

Past group members

  • Clémence Ligneul
  • Marco Palombo
  • Brice Tiret
  • Chloé Najac
  • Charlotte Marchadour 


Collaborations

  • 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)

Funding

  • ERC (INCELL project, 2013-2018)
  • ANR (HDeNERGY project, 2015-2019)

Recent publications

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.