Publications by authors named "Luisa Ciobanu"

39 Publications

Imaging of two samples with a single transmit/receive channel using coupled ceramic resonators for MR microscopy at 17.2 T.

NMR Biomed 2020 11 31;33(11):e4397. Epub 2020 Aug 31.

Neurospin, CEA, Gif-sur-Yvette, France, Gif-sur-Yvette, France.

In this paper we address the possibility to perform imaging of two samples within the same acquisition time using coupled ceramic resonators and one transmit/receive channel. We theoretically and experimentally compare the operation of our ceramic dual-resonator probe with a wire-wound solenoid probe, which is the standard probe used in ultrahigh-field magnetic resonance microscopy. We show that due to the low-loss ceramics used to fabricate the resonators, and a favorable distribution of the electric field within the conducting sample, a dual probe, which contains two samples, achieves an SNR enhancement by a factor close to the square root of 2 compared with a solenoid optimized for one sample.
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http://dx.doi.org/10.1002/nbm.4397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709743PMC
November 2020

Differential effects of aquaporin-4 channel inhibition on BOLD fMRI and diffusion fMRI responses in mouse visual cortex.

PLoS One 2020 21;15(5):e0228759. Epub 2020 May 21.

NeuroSpin/Joliot, CEA-Saclay Center, Gif-sur-Yvette, France.

The contribution of astrocytes to the BOLD fMRI and DfMRI responses in visual cortex of mice following visual stimulation was investigated using TGN-020, an aquaporin 4 (AQP4) channel blocker, acting as an astrocyte function perturbator. Under TGN-020 injection the amplitude of the BOLD fMRI response became significantly higher. In contrast no significant changes in the DfMRI responses and the electrophysiological responses were observed. Those results further confirm the implications of astrocytes in the neurovascular coupling mechanism underlying BOLD fMRI, but not in the DfMRI responses which remained unsensitive to astrocyte function perturbation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228759PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241787PMC
September 2020

Diffusion MRI reveals in vivo and non-invasively changes in astrocyte function induced by an aquaporin-4 inhibitor.

PLoS One 2020 15;15(5):e0229702. Epub 2020 May 15.

NeuroSpin/Joliot, CEA-Saclay Center, Gif-sur-Yvette, France.

The Glymphatic System (GS) has been proposed as a mechanism to clear brain tissue from waste. Its dysfunction might lead to several brain pathologies, including the Alzheimer's disease. A key component of the GS and brain tissue water circulation is the astrocyte which is regulated by acquaporin-4 (AQP4), a membrane-bound water channel on the astrocytic end-feet. Here we investigated the potential of diffusion MRI to monitor astrocyte activity in a mouse brain model through the inhibition of AQP4 channels with TGN-020. Upon TGN-020 injection, we observed a significant decrease in the Sindex, a diffusion marker of tissue microstructure, and a significant increase of the water diffusion coefficient (sADC) in cerebral cortex and hippocampus compared to saline injection. These results indicate the suitability of diffusion MRI to monitor astrocytic activity in vivo and non-invasively.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229702PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228049PMC
July 2020

A New Tool for In Vivo Study of Astrocyte Connexin 43 in Brain.

Sci Rep 2019 12 4;9(1):18292. Epub 2019 Dec 4.

Theranexus, 60 Avenue Rockefeller, 69008, Lyon, France.

Astrocytes are glial cells organized in dynamic and structured networks in the brain. These plastic networks, involving key proteins such as connexin 43 (Cx43), are engaged in fine neuronal tuning and have recently been considered as emerging therapeutic targets in central nervous system disorders. We developed and validated a new application of the manganese-enhanced magnetic resonance imaging (MEMRI) technique allowing in vivo investigations of astrocyte-neuron interactions through quantification of brain Cx43 functional activity. The proof of concept has been achieved by quantification of MEMRI signals in brain after either local astrocyte-specific Cx43 knockdown with shRNA or systemic administration of Cx43 blockers. Unilateral hippocampal Cx43 genetical silencing was associated with an ipsilateral local increase of MEMRI signal. Furthermore, Cx43 blockers also enhanced MEMRI signal responses in hippocampus. Altogether, these data reveal the MEMRI technique as a tool for quantitative imaging of in vivo Cx43-dependent function in astrocytes under physiological and pathological conditions.
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http://dx.doi.org/10.1038/s41598-019-54858-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892890PMC
December 2019

Enhancing surface coil sensitive volume with hybridized electric dipoles at 17.2 T.

J Magn Reson 2019 10 16;307:106567. Epub 2019 Aug 16.

CEA, DRF, JOLIOT, NeuroSpin, UNIRS, Université Paris-Saclay, Gif-sur-Yvette, France.

Preclinical MR applications at 17.2 T can require field of views on the order of a few square centimeters. This is a challenging task as the proton Larmor frequency reaches 730 MHz. Most of the protocols at such frequencies are performed with surface transceiver coils for which the sensitive volume and the signal to noise ratio (SNR) is given by their size. Here we propose an approach based on metamaterials in order to enhance the sensitive volume of a commercial surface coil for small animal imaging at 17.2 T. We designed a passive resonator composed of four hybridized electric dipoles placed onto the floor of the MRI bed. Combining numerical and experimental results on a phantom and in vivo, we demonstrate a 20% increase of the sensitive volume in depth and 25% along the rostro-caudal axis while maintaining more than 85% of the local SNR right beneath the surface coil plane. Moreover, our solution gives the ability to double the average SNR in the region between 1.2 and 2 cm away from the loop using a single layer of 1 mm thick metallic wires easy to design and manufacture.
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http://dx.doi.org/10.1016/j.jmr.2019.106567DOI Listing
October 2019

Systematic Analysis of the Improvements in Magnetic Resonance Microscopy with Ferroelectric Composite Ceramics.

Adv Mater 2019 Jul 17;31(30):e1900912. Epub 2019 May 17.

ITMO University, 197101, St. Petersburg, Russia.

The spatial resolution and signal-to-noise ratio (SNR) attainable in magnetic resonance microscopy (MRM) are limited by intrinsic probe losses and probe-sample interactions. In this work, the possibility to exceed the SNR of a standard solenoid coil by more than a factor-of-two is demonstrated theoretically and experimentally. This improvement is achieved by exciting the first transverse electric mode of a low-loss ceramic resonator instead of using the quasi-static field of the metal-wire solenoid coil. Based on theoretical considerations, a new probe for microscopy at 17 T is developed as a dielectric ring resonator made of ferroelectric/dielectric low-loss composite ceramics precisely tunable via temperature control. Besides the twofold increase in SNR, compared with the solenoid probe, the proposed ceramic probe does not cause static-field inhomogeneity and related image distortion.
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http://dx.doi.org/10.1002/adma.201900912DOI Listing
July 2019

Brain sugar consumption during neuronal activation detected by CEST functional MRI at ultra-high magnetic fields.

Sci Rep 2019 03 14;9(1):4423. Epub 2019 Mar 14.

NeuroSpin, Commissariat à l'Energie Atomique et aux Energies Alternatives, Univerisité Paris-Saclay, Gif-sur-Yvette, France.

Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) indirectly measures brain activity based on neurovascular coupling, a reporter that limits both the spatial and temporal resolution of the technique as well as the cellular and metabolic specificity. Emerging methods using functional spectroscopy (fMRS) and diffusion-weighted fMRI suggest that metabolic and structural modifications are also taking place in the activated cells. This paper explores an alternative metabolic imaging approach based on Chemical Exchange Saturation Transfer (CEST) to assess potential metabolic changes induced by neuronal stimulation in rat brains at 17.2 T. An optimized CEST-fMRI data acquisition and processing protocol was developed and used to experimentally assess the feasibility of glucoCEST-based fMRI. Images acquired under glucose-sensitizing conditions showed a substantial negative contrast that highlighted the same brain regions as those activated with BOLD-fMRI. We ascribe this novel fMRI contrast to CEST's ability to monitor changes in the local concentration of glucose, a metabolite closely coupled to neuronal activity. Our findings are in good agreement with literature employing other modalities. The use of CEST-based techniques for fMRI is not limited to glucose detection; other metabolic pathways involved in neuronal activation could be potentially probed. Moreover, being non invasive, it is conceivable that the same approach can be used for human studies.
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http://dx.doi.org/10.1038/s41598-019-40986-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418181PMC
March 2019

Mesoscopic and microscopic imaging of sensory responses in the same animal.

Nat Commun 2019 03 7;10(1):1110. Epub 2019 Mar 7.

INSERM U1128, Laboratory of Neurophysiology and New Microscopy, Université Paris Descartes, Paris, 75006, France.

Imaging based on blood flow dynamics is widely used to study sensory processing. Here we investigated the extent to which local neuronal and capillary responses (two-photon microscopy) are correlated to mesoscopic responses detected with fast ultrasound (fUS) and BOLD-fMRI. Using a specialized chronic olfactory bulb preparation, we report that sequential imaging of the same mouse allows quantitative comparison of odour responses, imaged at both microscopic and mesoscopic scales. Under these conditions, functional hyperaemia occurred at the threshold of neuronal activation and fUS-CBV signals could be detected at the level of single voxels with activation maps varying according to blood velocity. Both neuronal and vascular responses increase non-linearly as a function of odour concentration, whereas both microscopic and mesoscopic vascular responses are linearly correlated to local neuronal calcium. These data establish strengths and limits of mesoscopic imaging techniques to report neural activity.
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http://dx.doi.org/10.1038/s41467-019-09082-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405955PMC
March 2019

Spatial contribution of hippocampal BOLD activation in high-resolution fMRI.

Sci Rep 2019 02 28;9(1):3152. Epub 2019 Feb 28.

Commissariat à l'énergie atomique et aux energies alternatives, DRF, Joliot, NeuroSpin, Paris-Saclay University, Gif-sur-Yvette, France.

While the vascular origin of the BOLD-fMRI signal is established, the exact neurovascular coupling events contributing to this signal are still incompletely understood. Furthermore, the hippocampal spatial properties of the BOLD activation are not elucidated, although electrophysiology approaches have already revealed the precise spatial patterns of neural activity. High magnetic field fMRI offers improved contrast and allows for a better correlation with the underlying neuronal activity because of the increased contribution to the BOLD signal of small blood vessels. Here, we take advantage of these two benefits to investigate the spatial characteristics of the hippocampal activation in a rat model before and after changing the hippocampal plasticity by long-term potentiation (LTP). We found that the hippocampal BOLD signals evoked by electrical stimulation at the perforant pathway increased more at the radiatum layer of the hippocampal CA1 region than at the pyramidal cell layer. The return to the baseline of the hippocampal BOLD activation was prolonged after LTP induction compared with that before most likely due vascular or neurovascular coupling changes. Based on these results, we conclude that high resolution BOLD-fMRI allows the segregation of hippocampal subfields probably based on their underlying vascular or neurovascular coupling features.
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http://dx.doi.org/10.1038/s41598-019-39614-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395694PMC
February 2019

Intracellular manganese enhanced MRI signals reflect the frequency of action potentials in Aplysia neurons.

J Neurosci Methods 2018 02 14;295:121-128. Epub 2017 Dec 14.

NeuroSpin, CEA Saclay, 91191 Gif-sur-Yvette, France. Electronic address:

Background: Manganese-enhanced magnetic resonance imaging (MEMRI) is an increasingly popular alternative to standard functional MRI methods in animal studies. The contrast in MEMRI images is based on the accumulation of Mn ions inside neurons, and, since manganese can serve as calcium analogue, this accumulation reflects calcium dynamics providing versatile information about brain neuroarchitecture and functionality. However, despite its use as a functional imaging tool, the exact relationship between the MEMRI signal and neuronal activity remains elusive.

New Method: In order to better understand the mechanisms underlying Mn accumulation resulting in MEMRI signal enhancement we investigated single neuron responses of isolated Aplysia buccal ganglia subjected to chemical (dopamine) or electrical stimulation of an input nerve (oesophageal nerve). The elicited electrical activity that represents a fictive feeding was recorded with electrophysiological methods and the Mn uptake in individual neurons was evaluated with MEMRI at 17.2T.

Results & Comparison With Existing Method(s): We show a positive correlation between bursts of electrical activity and MEMRI signal intensity in identified neurons and demonstrate that the MEMRI signal reflects mainly fast and high membrane depolarization processes such as action potentials, and it is not sensitive to slow and small membrane depolarizations, such as post-synaptic potentials.
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http://dx.doi.org/10.1016/j.jneumeth.2017.12.008DOI Listing
February 2018

Modulation of water diffusion by activation-induced neural cell swelling in Aplysia Californica.

Sci Rep 2017 07 21;7(1):6178. Epub 2017 Jul 21.

NeuroSpin, Bât 145, Joliot Institute, CEA-Paris-Saclay Center, Point Courrier 156, 91191, Gif-sur-Yvette, France.

Diffusion functional magnetic resonance imaging (DfMRI) has been proposed as a method for functional neuroimaging studies, as an alternative to blood oxygenation level dependent (BOLD)-fMRI. DfMRI is thought to more directly reflect neural activation, but its exact mechanism remains unclear. It has been hypothesized that the water apparent diffusion coefficient (ADC) decrease observed upon neural activation results from swelling of neurons or neuron parts. To elucidate the origin of the DfMRI response at cellular level we performed diffusion MR microscopy at 17.2 T in Aplysia californica buccal ganglia and compared the water ADCs at cellular and ganglia levels before and after neuronal activation induced by perfusion with a solution containing dopamine. Neural cell swelling, evidenced from optical microscopy imaging, resulted in an intracellular ADC increase and an ADC decrease at ganglia level. Furthermore, the intracellular ADC increase was found to have a significant positive correlation with the increase in cell size. Our results strongly support the hypothesis that the ADC decrease observed with DfMRI upon neuronal activation at tissue level reflects activation-induced neural cell swelling.
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http://dx.doi.org/10.1038/s41598-017-05586-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522485PMC
July 2017

Quantitative DLA-based compressed sensing for T-weighted acquisitions.

J Magn Reson 2017 08 9;281:26-30. Epub 2017 May 9.

NeuroSpin, CEA Saclay, 91191 Gif-sur-Yvette, France; University Paris-Saclay, XI, 91450 Orsay, France. Electronic address:

High resolution Manganese Enhanced Magnetic Resonance Imaging (MEMRI), which uses manganese as a T contrast agent, has great potential for functional imaging of live neuronal tissue at single neuron scale. However, reaching high resolutions often requires long acquisition times which can lead to reduced image quality due to sample deterioration and hardware instability. Compressed Sensing (CS) techniques offer the opportunity to significantly reduce the imaging time. The purpose of this work is to test the feasibility of CS acquisitions based on Diffusion Limited Aggregation (DLA) sampling patterns for high resolution quantitative T-weighted imaging. Fully encoded and DLA-CS T-weighted images of Aplysia californica neural tissue were acquired on a 17.2T MRI system. The MR signal corresponding to single, identified neurons was quantified for both versions of the T weighted images. For a 50% undersampling, DLA-CS can accurately quantify signal intensities in T-weighted acquisitions leading to only 1.37% differences when compared to the fully encoded data, with minimal impact on image spatial resolution. In addition, we compared the conventional polynomial undersampling scheme with the DLA and showed that, for the data at hand, the latter performs better. Depending on the image signal to noise ratio, higher undersampling ratios can be used to further reduce the acquisition time in MEMRI based functional studies of living tissues.
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http://dx.doi.org/10.1016/j.jmr.2017.05.002DOI Listing
August 2017

A two-pool model to describe the IVIM cerebral perfusion.

J Cereb Blood Flow Metab 2017 Aug 1;37(8):2987-3000. Epub 2016 Jan 1.

1 NeuroSpin, CEA Saclay-Center, Gif-sur-Yvette, France.

IntraVoxel Incoherent Motion (IVIM) is a magnetic resonance imaging (MRI) technique capable of measuring perfusion-related parameters. In this manuscript, we show that the mono-exponential model commonly used to process IVIM data might be challenged, especially at short diffusion times. Eleven rat datasets were acquired at 7T using a diffusion-weighted pulsed gradient spin echo sequence with b-values ranging from 7 to 2500 s/mm at three diffusion times. The IVIM signals, obtained by removing the diffusion component from the raw MR signal, were fitted to the standard mono-exponential model, a bi-exponential model and the Kennan model. The Akaike information criterion used to find the best model to fit the data demonstrates that, at short diffusion times, the bi-exponential IVIM model is most appropriate. The results obtained by comparing the experimental data to a dictionary of numerical simulations of the IVIM signal in microvascular networks support the hypothesis that such a bi-exponential behavior can be explained by considering the contribution of two vascular pools: capillaries and somewhat larger vessels.
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http://dx.doi.org/10.1177/0271678X16681310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536805PMC
August 2017

In vivo online magnetic resonance quantification of absolute metabolite concentrations in microdialysate.

Sci Rep 2016 11 4;6:36080. Epub 2016 Nov 4.

ISM, UMR 5255, Université Bordeaux, 33076, Bordeaux, France.

In order to study metabolic processes in animal models of diseases and in patients, microdialysis probes have evolved as powerful tools that are minimally invasive. However, analyses of microdialysate, performed remotely, do not provide real-time monitoring of microdialysate composition. Microdialysate solutions can theoretically be analyzed online inside a preclicinal or clinical MRI scanner using MRS techniques. Due to low NMR sensitivity, acquisitions of real-time NMR spectra on very small solution volumes (μL) with low metabolite concentrations (mM range) represent a major issue. To address this challenge we introduce the approach of combining a microdialysis probe with a custom-built magnetic resonance microprobe that allows for online metabolic analysis (H and C) with high sensitivity under continuous flow conditions. This system is mounted inside an MRI scanner and allows performing simultaneously MRI experiments and rapid MRS metabolic analysis of the microdialysate. The feasibility of this approach is demonstrated by analyzing extracellular brain cancer cells (glioma) in vitro and brain metabolites in an animal model in vivo. We expect that our approach is readily translatable into clinical settings and can be used for a better and precise understanding of diseases linked to metabolic dysfunction.
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http://dx.doi.org/10.1038/srep36080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095764PMC
November 2016

DLA based compressed sensing for high resolution MR microscopy of neuronal tissue.

J Magn Reson 2015 Oct 31;259:186-91. Epub 2015 Aug 31.

Neurospin, CEA Saclay, 91191 Gif sur Yvette, France. Electronic address:

In this work we present the implementation of compressed sensing (CS) on a high field preclinical scanner (17.2 T) using an undersampling trajectory based on the diffusion limited aggregation (DLA) random growth model. When applied to a library of images this approach performs better than the traditional undersampling based on the polynomial probability density function. In addition, we show that the method is applicable to imaging live neuronal tissues, allowing significantly shorter acquisition times while maintaining the image quality necessary for identifying the majority of neurons via an automatic cell segmentation algorithm.
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http://dx.doi.org/10.1016/j.jmr.2015.08.012DOI Listing
October 2015

fMRI contrast at high and ultrahigh magnetic fields: insight from complementary methods.

Neuroimage 2015 Jun 18;113:37-43. Epub 2015 Mar 18.

Weizmann Institute of Science, Rehovot, Israel. Electronic address:

This manuscript examines the origins and nature of the function-derived activation detected by magnetic resonance imaging at ultrahigh fields using different encoding methods. A series of preclinical high field (7 T) and ultra-high field (17.2 T) fMRI experiments were performed using gradient echo EPI, spin echo EPI and spatio-temporally encoded (SPEN) strategies. The dependencies of the fMRI signal change on the strength of the magnetic field and on different acquisition and sequence parameters were investigated. Artifact-free rat brain images with good resolution in all areas, as well as significant localized activation maps upon forepaw stimulation, were obtained in a single scan using fully refocused SPEN sequences devoid of T2* effects. Our results showed that, besides the normal T2-weighted BOLD contribution that arises in spin-echo sequences, fMRI SPEN signals contain a strong component caused by apparent T1-related effects, demonstrating the potential of such technique for exploring functional activation in rodents and on humans at ultrahigh fields.
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http://dx.doi.org/10.1016/j.neuroimage.2015.03.018DOI Listing
June 2015

[The functional imaging of individual neurons within complex networks].

Med Sci (Paris) 2015 Jan 6;31(1):15-7. Epub 2015 Feb 6.

NeuroSpin, Commissariat à l'énergie atomique et aux énergies alternatives, 91191 Gif-sur-Yvette, France.

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http://dx.doi.org/10.1051/medsci/20153101004DOI Listing
January 2015

Sedation agents differentially modulate cortical and subcortical blood oxygenation: evidence from ultra-high field MRI at 17.2 T.

PLoS One 2014 22;9(7):e100323. Epub 2014 Jul 22.

NeuroSpin, Commissariat à l'Energie Atomique et aux Energies Alternatives, CEA Saclay, Gif-sur-Yvette, France; Equipe Avenir INSERM Bettencourt Schueller, NeuroSpin, Unité de Recherche en NeuroImagerie Applicative Clinique et Translationnelle (UNIACT), Gif-sur-Yvette, France; Department of Neurosurgery, Neuromodulation Unit, Foch Hospital, University of Versailles Saint-Quentin, Suresnes, France.

Background: Sedation agents affect brain hemodynamic and metabolism leading to specific modifications of the cerebral blood oxygenation level. We previously demonstrated that ultra-high field (UHF) MRI detects changes in cortical blood oxygenation following the administration of sedation drugs commonly used in animal research. Here we applied the UHF-MRI method to study clinically relevant sedation drugs for their effects on cortical and subcortical (thalamus, striatum) oxygenation levels.

Methods: We acquired T2*-weighted images of Sprague-Dawley rat brains at 17.2T in vivo. During each MRI session, rats were first anesthetized with isoflurane, then with a second sedative agent (sevoflurane, propofol, midazolam, medetomidine or ketamine-xylazine) after stopping isoflurane. We computed a T2*-oxygenation-ratio that aimed at estimating cerebral blood oxygenation level for each sedative agent in each region of interest: cortex, hippocampus, thalamus and striatum.

Results: The T2*-oxygenation-ratio was consistent across scan sessions. This ratio was higher with inhalational agents than with intravenous agents. Under sevoflurane and medetomidine, T2*-oxygenation-ratio was homogenous across the brain regions. Intravenous agents (except medetomidine) induced a T2*-oxygenation-ratio imbalance between cortex and subcortical regions: T2*-oxygenation-ratio was higher in the cortex than the subcortical areas under ketamine-xylazine; T2*-oxygenation-ratio was higher in subcortical regions than in the cortex under propofol or midazolam.

Conclusion: Preclinical UHF MRI is a powerful method to monitor the changes in cerebral blood oxygenation level induced by sedative agents across brain structures. This approach also allows for a classification of sedative agents based on their differential effects on cerebral blood oxygenation level.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0100323PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4106755PMC
March 2016

Functional magnetic resonance microscopy at single-cell resolution in Aplysia californica.

Proc Natl Acad Sci U S A 2014 Jun 28;111(23):8667-72. Epub 2014 May 28.

NeuroSpin, Commissariat à l'Energie Atomique et aux Energies Alternatives, 91191 Gif-sur-Yvette, France; and

In this work, we show the feasibility of performing functional MRI studies with single-cell resolution. At ultrahigh magnetic field, manganese-enhanced magnetic resonance microscopy allows the identification of most motor neurons in the buccal network of Aplysia at low, nontoxic Mn(2+) concentrations. We establish that Mn(2+) accumulates intracellularly on injection into the living Aplysia and that its concentration increases when the animals are presented with a sensory stimulus. We also show that we can distinguish between neuronal activities elicited by different types of stimuli. This method opens up a new avenue into probing the functional organization and plasticity of neuronal networks involved in goal-directed behaviors with single-cell resolution.
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http://dx.doi.org/10.1073/pnas.1403739111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060695PMC
June 2014

Characterization of glioma microcirculation and tissue features using intravoxel incoherent motion magnetic resonance imaging in a rat brain model.

Invest Radiol 2014 Jul;49(7):485-90

From the *Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan; †NeuroSpin, CEA-Saclay, Gif-sur-Yvette, France; ‡Equipe DEFI, INRIA Saclay Palaiseau, France; §Kyoto University Faculty of Medicine; and ∥Human Brain Research Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Purpose: Our aim was to investigate the pertinence of diffusion and perfusion magnetic resonance imaging (MRI) parameters obtained at 17.2 T in a 9L glioma rat brain tumor model to evaluate tumor tissue characteristics.

Materials And Methods: The local animal ethics advisory committee approved this study. 9L glioma cells were injected intracerebrally to 14 Fischer rats. The animals were imaged at 7 or 12 days after implantation on a 17.2-T MRI scanner, using 72 different b values (2-3025 s/mm(2)). The signal attenuation, S/So, was fitted using a kurtosis diffusion model (ADCo and K) and a biexponential diffusion model (fractions ffast and fslow and diffusion coefficients Dfast and Dslow) using b values greater than 300 s/mm(2). To bridge the 2 models, an average diffusion coefficient and a biexponential index were estimated from the biexponential model as ADCo and K equivalents, respectively. Intravoxel incoherent motion perfusion-related parameters were obtained from the residual signal at low b values, after the diffusion component has been removed. Diffusion and perfusion maps were generated for each fitted parameter on a pixel-by-pixel basis, and regions of interest were drawn in the tumor and contralateral side to retrieve diffusion and perfusion parameters. All rats were killed and cellularity and vascularity were quantitatively assessed using histology for comparison with diffusion and perfusion parameters.

Results: Intravoxel incoherent motion maps clearly highlighted tumor areas as generally heterogeneous, as confirmed by histology. For diffusion parameters, ADCo and were not significantly different between the tumor and contralateral side, whereas K in the tumor was significantly higher than in contralateral basal ganglia (P < 0.0001), as well as biexponential index (P < 0.001). ADCo and in the tumor at day 7 were significantly higher than at day 12 (P < 0.01 and P < 0.001, respectively). fIVIM in the tumor from the kurtosis diffusion model was significantly higher than in contralateral basal ganglia (P < 0.001). fIVIM in the tumor at day 7 was significantly higher than in the tumor at day 12 (P < 0.0001). There was no significant difference for D* between the tumor and contralateral side (P = 0.06). A significant negative correlation was found between tumor vascularity and fIVIM (P < 0.05) as well as between tumor cell count and (P < 0.01).

Conclusion: Quantitative non-Gaussian diffusion and perfusion MRI can provide valuable information on microvasculature and tissue structure to improve characterization of brain tumors.
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http://dx.doi.org/10.1097/RLI.0000000000000040DOI Listing
July 2014

Non-Gaussian diffusion imaging for enhanced contrast of brain tissue affected by ischemic stroke.

PLoS One 2014 27;9(2):e89225. Epub 2014 Feb 27.

Institute of Neuroscience and Medicine - 4, Forschungszentrum Juelich GmbH, Juelich, Germany ; Department of Neurology, Faculty of Medicine, JARA, RWTH Aachen University, Aachen, Germany.

Recent diffusion MRI studies of stroke in humans and animals have shown that the quantitative parameters characterising the degree of non-Gaussianity of the diffusion process are much more sensitive to ischemic changes than the apparent diffusion coefficient (ADC) considered so far as the "gold standard". The observed changes exceeded that of the ADC by a remarkable factor of 2 to 3. These studies were based on the novel non-Gaussian methods, such as diffusion kurtosis imaging (DKI) and log-normal distribution function imaging (LNDFI). As shown in our previous work investigating the animal stroke model, a combined analysis using two methods, DKI and LNDFI provides valuable complimentary information. In the present work, we report the application of three non-Gaussian diffusion models to quantify the deviations from the Gaussian behaviour in stroke induced by transient middle cerebral artery occlusion in rat brains: the gamma-distribution function (GDF), the stretched exponential model (SEM), and the biexponential model. The main goal was to compare the sensitivity of various non-Gaussian metrics to ischemic changes and to investigate if a combined application of several models will provide added value in the assessment of stroke. We have shown that two models, GDF and SEM, exhibit a better performance than the conventional method and allow for a significantly enhanced visualization of lesions. Furthermore, we showed that valuable information regarding spatial properties of stroke lesions can be obtained. In particular, we observed a stratified cortex structure in the lesions that were well visible in the maps of the GDF and SEM metrics, but poorly distinguishable in the ADC-maps. Our results provided evidence that cortical layers tend to be differently affected by ischemic processes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0089225PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937347PMC
October 2014

Effects of hypotonic stress and ouabain on the apparent diffusion coefficient of water at cellular and tissue levels in Aplysia.

NMR Biomed 2014 Mar 8;27(3):280-90. Epub 2014 Jan 8.

NeuroSpin, Commissariat à l'Energie Atomique et aux Energies Alternatives, Gif-sur-Yvette, France.

There is evidence that physiological or pathological cell swelling is associated with a decrease of the apparent diffusion coefficient (ADC) of water in tissues, as measured with MRI. However the mechanism remains unclear. Magnetic resonance microscopy, performed on small tissue samples, has the potential to distinguish effects occurring at cellular and tissue levels. A three-dimensional diffusion prepared fast imaging with steady-state free precession sequence for MR microscopy was implemented on a 17.2 T imaging system and used to investigate the effect of two biological challenges known to cause cell swelling, exposure to a hypotonic solution or to ouabain, on Aplysia nervous tissue. The ADC was measured inside isolated neuronal soma and in the region of cell bodies of the buccal ganglia. Both challenges resulted in an ADC increase inside isolated neuronal soma (+31 ± 24% and +30 ± 11%, respectively) and an ADC decrease at tissue level in the buccal ganglia (-12 ± 5% and -18 ± 8%, respectively). A scenario involving a layer of water molecules bound to the inflating cell membrane surface is proposed to reconcile this apparent discrepancy.
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http://dx.doi.org/10.1002/nbm.3061DOI Listing
March 2014

Relationship between the diffusion time and the diffusion MRI signal observed at 17.2 Tesla in the healthy rat brain cortex.

Magn Reson Med 2014 Aug 10;72(2):492-500. Epub 2013 Sep 10.

NeuroSpin, Commissariat à l'Energie Atomique et aux Energies Alternatives, Gif-sur-Yvette, France.

Purpose: To investigate the diffusion time dependency of water diffusion in cortical brain tissue.

Methods: We have combined an oscillating gradient spin-echo (OGSE) and a pulse gradient spin echo (PGSE) spin-echo sequence to acquire diffusion-weighted MRI images in vivo in healthy rat brains over a wide range of diffusion times (1.9-29.2 ms) and estimated the parameters of the biexponential and cumulant expansion diffusion MRI signal models. Diffusion images were obtained at 17.2 Tesla with maximum gradient strength of 1000 mT/m allowing 40 b values up to approximately 4000 s/mm(2).

Results: At all diffusion times the log plot of diffusion signal attenuation versus b value was curved, confirming that diffusion is not free, even at very short diffusion times. This suggests that the length scale of obstacles to diffusion must be smaller than the corresponding shortest observed diffusion distance (approximately 1.7 μm). The diffusion MRI signal was also not found in a steady-state, even at our longest diffusion time (29.2 ms), suggesting some degree of segregation of water in pools.

Conclusion: Overall, the results showed that the parameters derived from the two diffusion models could not well be related to specific tissue features. More specific models must be developed taking into account diffusion signal behavior at high b values and short diffusion times.
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http://dx.doi.org/10.1002/mrm.24921DOI Listing
August 2014

Water diffusion in brain cortex closely tracks underlying neuronal activity.

Proc Natl Acad Sci U S A 2013 Jul 25;110(28):11636-41. Epub 2013 Jun 25.

NeuroSpin, Bât 145, Commissariat à l'Energie Atomique-Saclay Center, 91191 Gif-sur-Yvette, France.

Neuronal activity results in a local increase in blood flow. This concept serves as the basis for functional MRI. Still, this approach remains indirect and may fail in situations interfering with the neurovascular coupling mechanisms (drugs, anesthesia). Here we establish that water molecular diffusion is directly modulated by underlying neuronal activity using a rat forepaw stimulation model under different conditions of neuronal stimulation and neurovascular coupling. Under nitroprusside infusion, a neurovascular-coupling inhibitor, the diffusion response and local field potentials were maintained, whereas the hemodynamic response was abolished. As diffusion MRI reflects interactions of water molecules with obstacles (e.g., cell membranes), the observed changes point to a dynamic modulation of the neural tissue structure upon activation, which remains to be investigated. These findings represent a significant shift in concept from the current electrochemical and neurovascular coupling principles used for brain imaging, and open unique avenues to investigate mechanisms underlying brain function.
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http://dx.doi.org/10.1073/pnas.1303178110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710802PMC
July 2013

Highlighting manganese dynamics in the nervous system of Aplysia californica using MEMRI at ultra-high field.

Neuroimage 2013 Aug 22;76:264-71. Epub 2013 Mar 22.

NeuroSpin, Commissariat à l'Energie Atomique et aux Energies Alternatives, 91191 Gif-sur-Yvette, France.

Exploring the pathways of manganese (Mn(2+)) transport in the nervous system becomes of interest as many recent studies use Mn(2+) as a neural tract tracer in mammals. In this study, we performed manganese enhanced MRI (MEMRI) at 17.2 T on the buccal ganglia of Aplysia californica. The main advantage of this model over mammalian systems is that it contains networks of large identified neurons. Using Mn(2+) retrograde transport along selected nerves, we first validated the mapping of motor neurons' axonal projections into peripheral nerves, previously obtained from optical imaging (Morton et al., 1991). This protocol was found not to alter the functional properties of the neuronal network. Second, we compared the Mn(2+) dynamics inside the ganglia in the presence or absence of chemical stimulation. We found that 2h of stimulation with the modulatory transmitter dopamine increased the extent of areas of intermediate signal enhancement caused by manganese accumulation. In the absence of dopamine, an overall decrease of the enhanced areas in favor of non-enhanced areas was found, as a result of natural Mn(2+) washout. This supports the hypothesis that, upon activation, Mn(2+) is released from labeled neurons and captured by other, initially unlabeled, neurons. However, the latter could not be clearly identified due to lack of sensitivity and multiplicity of possible pathways starting from labeled cells. Nonetheless, the Aplysia buccal ganglia remain a well-suited model for attempting to visualize Mn(2+) transport from neuron to neuron upon activation, as well as for studying dopaminergic modulation in a motor network.
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http://dx.doi.org/10.1016/j.neuroimage.2013.03.022DOI Listing
August 2013

Quantification of microvascular cerebral blood flux and late-stage tumor compartmentalization in 9L gliosarcoma using flow enhanced MRI.

NMR Biomed 2013 Jun 21;26(6):699-708. Epub 2013 Jan 21.

Commissariat a l'Energie Atomique/DSV, I2BM, NeuroSpin, LRMN, Gif sur Yvette, France.

Measurements of tumor microvasculature are important to obtain an understanding of tumor angiogenesis and for the evaluation of therapies. In this work, we characterize the evolution of the microvascular flux at different stages of tumor growth in the 9L rat brain tumor model. The absolute quantification of cerebral blood flux is achieved with MRI at 7 T using the flow enhanced signal intensity (FENSI) method. FENSI flux maps were obtained between 5 and 14 days after glioma cell inoculation. Based on cerebral blood flux maps, we highlighted two main stages of tumor growth, below and above 3 mm, presenting distinct flux patterns and vascular properties. No significant difference emerged from the group analysis performed on the data collected at an early developmental stage (tumor size < 3 mm) when compared with healthy tissue. At a late developmental stage (tumor size > 3 mm), we observed a significant decrease in the cerebral blood flux inside the gliosarcoma (-33%, p < 0.01) and compartmentalization of the tumor (p < 0.05). FENSI flux maps delineated a low-flux tumor core (58 ± 17 μL/min/cm(2) ) and higher vascularized regions around the tumor periphery (85 ± 21 μL/min/cm(2) ). Histology was performed on 11 animals to finely probe the intratumor heterogeneity and microvessel density, and the results were compared with the information derived from FENSI flux maps. The hyper- and hypoperfused tumor regions revealed with FENSI at the late tumor developmental stage correlated well with the ratios of high and low blood vessel density (R(2) = 0.41) and fractional vascular surface (R(2) = 0.67) observed with fluorescence microscopy [cluster of differentiation 31 (CD31) staining].
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http://dx.doi.org/10.1002/nbm.2915DOI Listing
June 2013

Experimental demonstration of diffusion signal enhancement in 2D DESIRE images.

J Magn Reson 2012 May 20;218:44-8. Epub 2012 Mar 20.

NeuroSpin, Commissariat à l'Energie Atomique et aux Energies Alternatives, 91191 Gif-sur-Yvette, France.

In magnetic resonance microscopy based on conventional Fourier encoding techniques, molecular self-diffusion leads to a loss in signal to noise ratio while also limiting the spatial resolution. As opposed to standard diffusion-weighted sequences, the DESIRE (Diffusion Enhancement of SIgnal and REsolution) method gains signal through diffusion via a signal difference measurement, corresponding to the total number of spins saturated by a localized pulse applied for a given amount of time. The higher the diffusion coefficient at that location, the larger the number of spins effectively saturated and thus the higher the difference in signal. While the method has been previously demonstrated in 1D, the availability of higher magnetic fields and gradient strengths has recently brought its development within reach in 2D. Here we report the implementation of 2D DESIRE and the first experimental evaluation of enhancements in water and thin silicone oil. Enhancement levels obtained by saturating a 60 μm diameter region (effectively ~140 μm) and allowing diffusion lengths of 28 μm or 7 μm, respectively, are consistent with theoretical predictions. The typical enhancement values are 100% in water and 20% in silicone oil.
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http://dx.doi.org/10.1016/j.jmr.2012.03.004DOI Listing
May 2012

Diffusion kurtosis imaging and log-normal distribution function imaging enhance the visualisation of lesions in animal stroke models.

NMR Biomed 2012 Nov 27;25(11):1295-304. Epub 2012 Mar 27.

Institute of Neuroscience and Medicine - 4, Forschungszentrum Juelich GmbH, Juelich, Germany.

In this work, we report a case study of a stroke model in animals using two methods of quantification of the deviations from Gaussian behaviour: diffusion kurtosis imaging (DKI) and log-normal distribution function imaging (LNDFI). The affected regions were predominantly in grey rather than in white matter. The parameter maps were constructed for metrics quantifying the apparent diffusivity (evaluated from conventional diffusion tensor imaging, DKI and LNDFI) and for those quantifying the degree of deviations (mean kurtosis and a parameter σ characterising the width of the distribution). We showed that both DKI and LNDFI were able to dramatically enhance the visualisation of ischaemic lesions in comparison with conventional methods. The largest relative change in the affected versus healthy regions was observed in the mean kurtosis values. The average changes in the mean kurtosis and σ values in the lesions were a factor of two to three larger than the relative changes observed in the mean diffusivity. In conclusion, the applied methods promise valuable perspectives in the assessment of stroke.
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http://dx.doi.org/10.1002/nbm.2802DOI Listing
November 2012

Effects of anesthetic agents on brain blood oxygenation level revealed with ultra-high field MRI.

PLoS One 2012 12;7(3):e32645. Epub 2012 Mar 12.

NeuroSpin, Commissariat à l'Energie Atomique et aux Energies Alternatives, Gif-sur-Yvette, France.

During general anesthesia it is crucial to control systemic hemodynamics and oxygenation levels. However, anesthetic agents can affect cerebral hemodynamics and metabolism in a drug-dependent manner, while systemic hemodynamics is stable. Brain-wide monitoring of this effect remains highly challenging. Because T(2)*-weighted imaging at ultra-high magnetic field strengths benefits from a dramatic increase in contrast to noise ratio, we hypothesized that it could monitor anesthesia effects on brain blood oxygenation. We scanned rat brains at 7T and 17.2T under general anesthesia using different anesthetics (isoflurane, ketamine-xylazine, medetomidine). We showed that the brain/vessels contrast in T(2)*-weighted images at 17.2T varied directly according to the applied pharmacological anesthetic agent, a phenomenon that was visible, but to a much smaller extent at 7T. This variation is in agreement with the mechanism of action of these agents. These data demonstrate that preclinical ultra-high field MRI can monitor the effects of a given drug on brain blood oxygenation level in the absence of systemic blood oxygenation changes and of any neural stimulation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0032645PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299673PMC
August 2012

The translocator protein ligand [¹⁸F]DPA-714 images glioma and activated microglia in vivo.

Eur J Nucl Med Mol Imaging 2012 May 21;39(5):811-23. Epub 2012 Jan 21.

Inserm, U1023, Laboratoire d'Imagerie Moléculaire Expérimentale, Université Paris Sud, Orsay, France.

Purpose: In recent years there has been an increase in the development of radioligands targeting the 18-kDa translocator protein (TSPO). TSPO expression is well documented in activated microglia and serves as a biomarker for imaging neuroinflammation. In addition, TSPO has also been reported to be overexpressed in a number of cancer cell lines and human tumours including glioma. Here we investigated the use of [(18)F]DPA-714, a new TSPO positron emission tomography (PET) radioligand to image glioma in vivo.

Methods: We studied the uptake of [(18)F]DPA-714 in three different rat strains implanted with 9L rat glioma cells: Fischer (F), Wistar (W) and Sprague Dawley (SD) rats. Dynamic [(18)F]DPA-714 PET imaging, kinetic modelling of PET data and in vivo displacement studies using unlabelled DPA-714 and PK11195 were performed. Validation of TSPO expression in 9L glioma cell lines and intracranial 9L gliomas were investigated using Western blotting and immunohistochemistry of brain tissue sections.

Results: All rats showed significant [(18)F]DPA-714 PET accumulation at the site of 9L tumour implantation compared to the contralateral brain hemisphere with a difference in uptake among the three strains (F > W > SD). The radiotracer showed high specificity for TSPO as demonstrated by the significant reduction of [(18)F]DPA-714 binding in the tumour after administration of unlabelled DPA-714 or PK11195. TSPO expression was confirmed by Western blotting in 9L cells in vitro and by immunohistochemistry ex vivo.

Conclusion: The TSPO radioligand [(18)F]DPA-714 can be used for PET imaging of intracranial 9L glioma in different rat strains. This preclinical study demonstrates the feasibility of employing [(18)F]DPA-714 as an alternative radiotracer to image human glioma.
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http://dx.doi.org/10.1007/s00259-011-2041-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3326235PMC
May 2012