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ABSTRACT: Nemaline myopathy (NM) is the most common disease entity among non-dystrophic skeletal muscle congenital diseases. Mutations in the skeletal muscle a-actin gene (ACTA1) account for ,25% of all NM cases and are the most frequent cause of severe forms of NM. So far, the mechanisms underlying muscle weakness in NM patients remain unclear. Additionally, recent Magnetic Resonance Imaging (MRI) studies reported a progressive fatty infiltration of skeletal muscle with a specific muscle involvement in patients with ACTA1 mutations. We investigated strictly noninvasively the gastrocnemius muscle function of a mouse model carrying a mutation in the ACTA1 gene (H40Y). Skeletal muscle anatomy (hindlimb muscles and fat volumes) and energy metabolism were studied using MRI and 31 Phosphorus magnetic resonance spectroscopy. Skeletal muscle contractile performance was investigated while applying a force-frequency protocol (from 1–150 Hz) and a fatigue protocol (80 stimuli at 40 Hz). H40Y mice showed a reduction of both absolute (240%) and specific (225%) maximal force production as compared to controls. Interestingly, muscle weakness was associated with an improved resistance to fatigue (+40%) and an increased energy cost. On the contrary, the force frequency relationship was not modified in H40Y mice and the extent of fatty infiltration was minor and not different from the WT group. We concluded that the H40Y mouse model does not reproduce human MRI findings but shows a severe muscle weakness which might be related to an alteration of intrinsic muscular properties. The increased energy cost in H40Y mice might be related to either an impaired mitochondrial function or an alteration at the cross-bridges level. Overall, we provided a unique set of anatomic, metabolic and functional biomarkers that might be relevant for monitoring the progression of NM disease but also for assessing the efficacy of potential therapeutic interventions at a preclinical level.
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ABSTRACT: PURPOSE: Quantitative measure of blood flow provides important information regarding renal function, nephropathies and viability of kidney transplantation. Therefore, a method that would allow quantitative and reliable assessment of the renal microvascular perfusion would be very valuable. Arterial spin labeling Magnetic Resonance Imaging has started to be widely used for human studies. For rodents though, despite the increasing number of transgenic mouse models, renal perfusion Magnetic Resonance Imaging has been only sparsely reported. This study investigated the use of FAIR (flow-sensitive alternating inversion recovery) and pseudo-continuous arterial spin labeling (pCASL) for mouse renal blood flow measurements. METHODS: FAIR and pCASL were compared in terms of sensitivity, absolute quantification, reproducibility and flexibility of implementation. Multislice and coronal imaging were also investigated. Studies were performed at 11.75 T with volumic transmitter/receiver radiofrequency coils and fast imaging. RESULTS: pCASL demonstrated better experimental flexibility and higher sensitivity compared to FAIR (> +20%). Renal blood flow values in the range of 550-750 mL/100 g/min for the cortex and of 140-230 mL/100 g/min for the medulla, consistent with literature data, were measured. CONCLUSION: pCASL was successfully applied at very high field for mouse renal blood flow measurements, demonstrating high sensitivity, flexibility and multislice imaging capability. pCASL may be considered as a method of choice for mouse kidney perfusion studies. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.
Magnetic Resonance in Medicine 04/2013; · 2.96 Impact Factor
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ABSTRACT: Arterial spin labeling has been developed and used for the quantitative and completely noninvasive assessment of myocardial perfusion in vivo. Here we propose a novel arterial spin labeling method called cine-ASL, which is based on an electrocardiogram-gated steady-pulsed labeling approach combined with simultaneous readout over the cardiac cycle using cine-fast low-angle shot. This method led to shorter acquisition times than the previously used Look-Locker flow-sensitive alternating inversion recovery gradient-echo technique while preserving spatial resolution and robustness with respect to cardiac motion. High resolution perfusion mapping (in-plane resolution = 195 μm × 391 μm) was carried out with both techniques at 4.7 T in a group of 14 healthy mice. Mean perfusion values were 5.0 ± 0.8 mL g(-1) min(-1) with cine-ASL and 5.9 ± 1.4 mL g(-1) min(-1) with Look-Locker flow-sensitive alternating inversion recovery. In one animal, physiological stress was induced with higher anesthetic concentration to evaluate the response of both methods under vasodilation. Global myocardial perfusion increased from 5.6 to 16.0 mL g(-1) min(-1) with cine-ASL and from 6.3 to 18.7 mL g(-1) min(-1) with Look-Locker flow-sensitive alternating inversion recovery. Although this original scheme requires a separate T(1) measurement to be fully quantitative, it improves arterial spin labeling sensitivity while maintaining compatibility with motion constraints in cardiac MRI in small rodents. Magn Reson Med, 2012. © 2012 Wiley Periodicals, Inc.
Magnetic Resonance in Medicine 01/2013; · 2.96 Impact Factor
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ABSTRACT: Many diseases, including brain disorders, are associated with perturbations of tissue metabolism. However, an often overlooked issue is the impact that inflammations outside the brain may have on brain metabolism. Our main goal was to study similarities and differences between brain metabolite profiles of animals suffering from experimental autoimmune encephalomyelitis (EAE) and adjuvant arthritis (AA) in Lewis rat models. Our principal objective was the determination of molecular protagonists involved in the metabolism underlying these diseases. EAE was induced by intraplantar injection of complete Freund's adjuvant (CFA) and spinal-cord homogenate (SC-H), whereas AA was induced by CFA only. Naive rats served as controls (n = 9 for each group). Two weeks after inoculation, animals were sacrificed, and brains were removed and processed for metabolomic analysis by NMR spectroscopy or for immunohistochemistry. Interestingly, both inflammatory diseases caused similar, though not identical, changes in metabolites involved in regulation of brain cell size and membrane production: among the osmolytes, taurine and the neuronal marker, -acetylaspartate, were decreased, and the astrocyte marker, -inositol, slightly increased in both inoculated groups compared with controls. Also ethanolamine-containing phospholipids, sources of inflammatory agents, and several glycolytic metabolites were increased in both inoculated groups. By contrast, the amino acids, aspartate and isoleucine, were less concentrated in CFA/SC-H and control vs. CFA rats. Our results suggest that inflammatory brain metabolite profiles may indicate the existence of either cerebral (EAE) or extra-cerebral (AA) inflammation. These inflammatory processes may act through distinct pathways that converge toward similar brain metabolic profiles. Our findings open new avenues for future studies aimed at demonstrating whether brain metabolic effects provoked by AA are pain/stress-mediated and/or due to the presence of systemic proinflammatory molecules. Regardless of the nature of these mechanisms, our findings may be of interest for future clinical studies, e.g. by magnetic resonance spectroscopy.
PLoS ONE 01/2013; 8(2):e56101. · 4.09 Impact Factor
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ABSTRACT: Nemaline myopathy (NM) is the most common disease entity among non-dystrophic skeletal muscle congenital diseases. Mutations in the skeletal muscle α-actin gene (ACTA1) account for ∼25% of all NM cases and are the most frequent cause of severe forms of NM. So far, the mechanisms underlying muscle weakness in NM patients remain unclear. Additionally, recent Magnetic Resonance Imaging (MRI) studies reported a progressive fatty infiltration of skeletal muscle with a specific muscle involvement in patients with ACTA1 mutations. We investigated strictly noninvasively the gastrocnemius muscle function of a mouse model carrying a mutation in the ACTA1 gene (H40Y). Skeletal muscle anatomy (hindlimb muscles and fat volumes) and energy metabolism were studied using MRI and (31)Phosphorus magnetic resonance spectroscopy. Skeletal muscle contractile performance was investigated while applying a force-frequency protocol (from 1-150 Hz) and a fatigue protocol (80 stimuli at 40 Hz). H40Y mice showed a reduction of both absolute (-40%) and specific (-25%) maximal force production as compared to controls. Interestingly, muscle weakness was associated with an improved resistance to fatigue (+40%) and an increased energy cost. On the contrary, the force frequency relationship was not modified in H40Y mice and the extent of fatty infiltration was minor and not different from the WT group. We concluded that the H40Y mouse model does not reproduce human MRI findings but shows a severe muscle weakness which might be related to an alteration of intrinsic muscular properties. The increased energy cost in H40Y mice might be related to either an impaired mitochondrial function or an alteration at the cross-bridges level. Overall, we provided a unique set of anatomic, metabolic and functional biomarkers that might be relevant for monitoring the progression of NM disease but also for assessing the efficacy of potential therapeutic interventions at a preclinical level.
PLoS ONE 01/2013; 8(4):e61517. · 4.09 Impact Factor
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ABSTRACT: In small rodent myocardial perfusion studies, the most widely used method is based on Look-Locker measurements of the magnetization recovery after FAIR preparation, which bears limitations regarding acquisition efficiency due to the pulsed arterial spin labeling nature of the sequence. To improve efficiency, this two-article set proposes a new steady-pulsed arterial spin labeling scheme using a cine readout incorporating one tagging pulse per heart cycle. In this part, we derive a theoretical description of the magnetization time evolution in such a scheme. The combination of steady-pulsed labeling and cine readout drives tissue magnetization into a stationary regime that explicitly depends on perfusion. In comparison with dedicated experiments on the mouse heart, the model is discussed and validated for perfusion quantification. The model predicts that in this regime, signal is independent of irregular dynamics occurring during acquisition, such as heart rate variations or arterial input function. Optimization of the sequence offers the possibility to increase the signal to noise ratio by efficient signal averaging. The sensitivity of this new method is shown to be more than three times larger than previously used techniques. Magn Reson Med, 2012. © 2012 Wiley Periodicals, Inc.
Magnetic Resonance in Medicine 12/2012; · 2.96 Impact Factor
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ABSTRACT: Our objective was to identify and quantify phospholipids in milk from different species (human HM, cow CoM, camel CaM, and mare MM) using an optimised 31P NMR spectroscopy procedure. The phospholipid fingerprints were species-specific with a broader variety of classes found in HM and MM; HM and CaM were richer in sphingomyelin (78.3 and 117.5 μg/ml) and plasmalogens (27.3 and 24 μg/ml), possibly important for infant development. Total phospholipid content was higher in CaM (0.503 mM) and lower in MM (0.101 mM) compared to HM (0.324 mM) or CoM (0.265 mM). Our optimised method showed good sensitivity, high resolution, and easy sample preparation with minimal loss of target molecules. It is suitable for determining the accurate composition of a large number of bioactive phospholipids with putative health benefits, including plasmalogens, and should aid in selecting appropriate ingredient sources for infant milk substitutes or fortifiers, and for functional foods dedicated to adults.
Food Chemistry 12/2012; 135(3):1777–1783. · 3.65 Impact Factor
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Magnetic Resonance Imaging 08/2012; · 1.99 Impact Factor
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Pediatric Research 08/2012; 72(2):221. · 2.70 Impact Factor
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Wafaa Zaaraoui,
Simon Konstandin,
Bertrand Audoin,
Armin M Nagel,
Audrey Rico,
Irina Malikova,
Elisabeth Soulier,
Patrick Viout,
Sylviane Confort-Gouny, Patrick J Cozzone,
Jean Pelletier,
Lothar R Schad,
Jean-Philippe Ranjeva
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ABSTRACT: To quantify brain sodium accumulations and characterize for the first time the spatial location of sodium abnormalities at different stages of relapsing-remitting (RR) multiple sclerosis (MS) by using sodium 23 ((23)Na) magnetic resonance (MR) imaging.
This study was approved by the local committee on ethics, and written informed consent was obtained from all participants. Three-dimensional (23)Na MR imaging data were obtained with a 3.0-T unit in two groups of patients with RR MS-14 with early RR MS (disease duration <5 years) and 12 with advanced RR MS (disease duration >5 years)-and 15 control subjects. Quantitative assessment of total sodium concentration (TSC) levels within compartments (MS lesions, white matter [WM], and gray matter [GM]) as well as statistical mapping analyses of TSC abnormalities were performed.
TSC was increased inside demyelinating lesions in both groups of patients, whereas increased TSC was observed in normal-appearing WM and GM only in those with advanced RR MS. In patients, increased TSC inside GM was correlated with disability (as determined with the Expanded Disability Status Scale [EDSS] score; P = .046, corrected) and lesion load at T2-weighted imaging (P = .003, corrected) but not with disease duration (P = .089, corrected). Statistical mapping analysis showed confined TSC increases inside the brainstem, cerebellum, and temporal poles in early RR MS and widespread TSC increases that affected the entire brain in advanced RR MS. EDSS score correlated with TSC increases inside motor networks.
TSC accumulation dramatically increases in the advanced stage of RR MS, especially in the normal-appearing brain tissues, concomitant with disability. Brain sodium MR imaging may help monitor the occurrence of tissue injury and disability.
Radiology 07/2012; 264(3):859-67. · 5.73 Impact Factor
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ABSTRACT: MR spectroscopy allows a noninvasive assessment of metabolic information in healthy and pathological central nervous system. Whereas MR spectroscopy has been extensively applied in the brain, only few spectroscopic studies of the spinal cord (SC) have been performed so far. For mice, due to additional technical challenges, in vivo (1) H SC MRS has not yet been reported. In this work, the feasibility of short echo time localized proton magnetic resonance spectroscopy using Point RESolved Spectroscopy sequence for the examination of mouse cervical SC at 11.75 T is presented. Several optimizations were performed to improve the static field homogeneity, to reduce physiological motion effects and lipid contaminations arising from SC surrounding tissues, and to provide a careful metabolic quantification. Satisfactory spectrum quality was obtained. The described protocol allowed reliable quantification of five metabolites in the cervical SC. The mean reproducibility regarding the quantification of tNAA, tCr and tCho was ≥ 80%, > 70% for mI and > 55% for Glu, whereas the intersubject variabilities were ≤ 21%. The application of this protocol to transgenic mouse models in pathological conditions such as SC injury or neurodegenerative diseases may thus provide complementary information to MRI and increase our understanding of such pathologies. Magn Reson Med, 2012. © 2012 Wiley Periodicals, Inc.
Magnetic Resonance in Medicine 06/2012; · 2.96 Impact Factor
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Sok-Sithikun Bun,
Frank Kober,
Alexis Jacquier,
Leon Espinosa,
Jérôme Kalifa,
Marie-France Bonzi,
Francis Kopp,
Nathalie Lalevee,
Stephane Zaffran,
Jean-Claude Deharo, Patrick J Cozzone,
Monique Bernard
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ABSTRACT: The aim of the study was to assess the value of in vivo T2 measurements to noninvasively quantify myocardial fibrosis in diabetic mice at 11.75 T. Diabetic cardiomyopathy is characterized by extracellular matrix alteration and microcirculation impairment. These conditions might provide electrical heterogeneity, which is a substrate for arrhythmogenesis. T1 mapping has been proposed to quantify diffuse myocardial fibrosis in cardiac diseases but has several limitations. T2 measurement may represent an alternative for fibrosis quantification at high magnetic field.
A magnetic resonance imaging protocol including in vivo T2 measurements at 11.75 T was performed in 9 male C57BL/6J mice after 8 weeks of streptozotocin-induced diabetes and in 9 control mice. Programmed ventricular stimulation was performed in both groups. T2 measurements were compared with histologic quantification of fibrosis using picrosirius red staining.
Myocardial T2 was significantly lower in diabetic mice (13.8 ± 2.8 ms) than in controls (18.9 ± 2.3 ms, P < 0.001). There was a good correlation between T2 and fibrosis area obtained by histopathology (R = 0.947, P < 0.001). During programmed ventricular stimulation, 3 nonsustained ventricular tachycardias were induced in diabetic mice versus none in the control group.
The in vivo T2 relaxation time strongly correlated with myocardial fibrosis area assessed with histologic staining in diabetic mice.
Investigative radiology 05/2012; 47(5):319-23. · 4.85 Impact Factor
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ABSTRACT: Magnetic resonance imaging (MRI) has considerably improved the diagnosis and monitoring of multiple sclerosis (MS). Conventional
MRI such as T2-weighted and gadolinium-enhanced T1-weighted sequences detect focal lesions of the white matter, damage of the blood–brain barrier, and tissue loss and inflammatory
activity within lesions. However, these conventional MRI metrics lack the specificity required for characterizing the underlying
pathophysiology, especially diffuse damage occurring throughout the whole central nervous system. To overcome these limitations,
advanced MRI techniques have been developed to get more sensitive and specific parameters of focal and diffuse brain damage.
Among these techniques, magnetization transfer imaging, diffusion MRI, functional MRI, and magnetic resonance spectroscopy
are the most significant. In this article, we provide an overview of these advanced MRI techniques and their contribution
to the better characterization and understanding of MS.
KeywordsMultiple sclerosis-MRI-Magnetization transfer imaging-Diffusion MRI-Functional MRI-MR spectroscopy
Biophysical Reviews 04/2012; 2(2):83-90.
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ABSTRACT: MR spectroscopy of the posterior fossa is pitted with numerous technical difficulties. It is, however, of great clinical interest
in the study of the degenerative diseases and tumors of this area. We have developed a method to perform 2D CSI of this area,
by using a sagittal slice and a careful positioning of outer volume saturation. We performed this acquisition in 30 healthy
volunteers to determine the normal metabolic ratios in five voxels of this area (mesencephalon. pons. medulla oblongata, vermis,
cerebellar white matter). The main technical difficulty was magnetic field inhomogeneity in the lower brainstem generated
by dental alloys. However, 88% of the voxels were of sufficient quality to be analyzed. The statistically significant regional
variations were a higher NAA/Cr ratio in the pons than in the medulla oblongata, higher Cho/Cr in the pons than in the mesencephalon
and higher Cho/ Cr in the cerebellar white matter than in the vermis. We conclude that 2D CSI of the brainstem, although technically
delicate can be performed in most patients.
MAGMA Magnetic Resonance Materials in Physics Biology and Medicine 04/2012; 13(2):127-133. · 1.88 Impact Factor
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ABSTRACT: To better understand the mechanisms underlying the pulmonary O(2) uptake (V(O(2P))) slow component during high-intensity exercise, we used (31)P magnetic resonance spectroscopy, gas exchange, surface electromyography and near-infrared spectroscopy measurements to examine the potential relationship between the slow components of V(O(2P)) and phosphocreatine (PCr), muscle recruitment and tissue oxygenation in endurance-trained athletes and sedentary subjects. Specifically, six endurance-trained and seven sedentary subjects performed a dynamic high-intensity exercise protocol during 6 min at an exercise intensity corresponding to 35-40% of knee-extensor maximal voluntary contraction. The slow component of V(O(2P))(117 ± 60 ml min(-1), i.e. 20 ± 10% of the total response) was associated with a paradoxical PCr resynthesis in endurance-trained athletes (-0.90 ± 1.27 mm, i.e. -12 ± 16% of the total response). Meanwhile, oxygenated haemoglobin increased throughout the second part of exercise and was significantly higher at the end of exercise compared with the value at 120 s (P < 0.05), whereas the integrated EMG was not significantly changed throughout exercise. In sedentary subjects, a slow component was simultaneously observed for V(O(2P)) and [PCr] time-dependent changes (208 ± 14 ml min(-1), i.e. 38 ± 18% of the total V(O(2P))response, and 1.82 ± 1.39 mm, i.e. 16 ± 13% of the total [PCr] response), but the corresponding absolute or relative amplitudes were not correlated. The integrated EMG was significantly increased throughout exercise in sedentary subjects. Taken together, our results challenge the hypothesis of a mechanistic link between [PCr] and V(O(2P)) slow components and demonstrate that, as a result of a tighter metabolic control and increased O(2) availability, the [PCr] slow component can be minimized in endurance-trained athletes while the V(O(2P)) slow component occurs.
Experimental physiology 04/2012; 97(8):955-69. · 3.17 Impact Factor
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Delphine Wybrecht,
Françoise Reuter,
Wafaa Zaaraoui,
Anthony Faivre,
Lydie Crespy,
Audrey Rico,
Irina Malikova,
Sylviane Confort-Gouny,
Elisabeth Soulier, Patrick J Cozzone,
Jean Pelletier,
Jean-Philippe Ranjeva,
Bertrand Audoin
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ABSTRACT: The ability of conventional magnetic resonance imaging (MRI) to predict subsequent physical disability and cognitive deterioration after a clinically isolated syndrome (CIS) is weak.
We aimed to investigate whether conventional MRI changes over 1 year could predict cognitive and physical disability 5 years later in CIS. We performed analyses using a global approach (T(2) lesion load, number of T(2) lesions), but also a topographic approach.
This study included 38 patients with a CIS. At inclusion, 10 out of 38 patients fulfilled the 2010 revised McDonald's criteria for the diagnosis of multiple sclerosis. Expanded Disability Status Scale (EDSS) evaluation was performed at baseline, year 1 and year 5, and cognitive evaluation at baseline and year 5. T(2)-weighted MRI was performed at baseline and year 1. We used voxelwise analysis to analyse the predictive value of lesions location for subsequent disability.
Using the global approach, no correlation was found between MRI and clinical data. The occurrence or growth of new lesions in the brainstem was correlated with EDSS changes over the 5 years of follow-up. The occurrence or growth of new lesions in cerebellum, thalami, corpus callosum and frontal lobes over 1 year was correlated with cognitive impairment at 5 years.
The assessment of lesion location at the first stage of multiple sclerosis may be of value to predict future clinical disability.
Multiple Sclerosis 03/2012; 18(11):1585-91. · 4.26 Impact Factor
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Anthony Faivre,
Audrey Rico,
Wafaa Zaaraoui,
Lydie Crespy,
Françoise Reuter,
Delphine Wybrecht,
Elisabeth Soulier,
Irina Malikova,
Sylviane Confort-Gouny, Patrick J Cozzone,
Jean Pelletier,
Jean-Philippe Ranjeva,
Bertrand Audoin
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ABSTRACT: The present study aims to determine the clinical counterpart of brain resting-state networks reorganization recently evidenced in early multiple sclerosis.
Thirteen patients with early relapsing-remitting multiple sclerosis and 14 matched healthy controls were included in a resting state functional MRI study performed at 3 T. Data were analyzed using group spatial Independent Component Analysis using concatenation approach (FSL 4.1.3) and double regression analyses (SPM5) to extract local and global levels of connectivity inside various resting state networks (RSNs). Differences in global levels of connectivity of each network between patients and controls were assessed using Mann-Whitney U-test. In patients, relationship between clinical data (Expanded Disability Status Scale and Multiple Sclerosis Functional Composite Score - MSFC) and global RSN connectivity were assessed using Spearman rank correlation.
Independent component analysis provided eight consistent neuronal networks involved in motor, sensory and cognitive processes. For seven RSNs, the global level of connectivity was significantly increased in patients compared with controls. No significant decrease in RSN connectivity was found in early multiple sclerosis patients. MSFC values were negatively correlated with increased RSN connectivity within the dorsal frontoparietal network (r = -0.811, p = 0.001), the right ventral frontoparietal network (r = - 0.587, p = 0.045) and the prefronto-insular network (r = -0.615, p = 0.033).
This study demonstrates that resting state networks reorganization is strongly associated with disability in early multiple sclerosis. These findings suggest that resting state functional MRI may represent a promising surrogate marker of disease burden.
Multiple Sclerosis 02/2012; 18(9):1251-8. · 4.26 Impact Factor
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ABSTRACT: Focal cortical dysplasia (FCD), dysembryoplastic neuroepithelial tumors (DNTs), and gangliogliomas (GGs) share many clinical features, and the presurgical differential diagnosis of these lesions using conventional magnetic resonance imaging (MRI) is challenging in some cases. The purpose of this work was thus to evaluate the capacity of diffusion-weighted imaging (DWI) and proton magnetic resonance spectroscopy (MRS) to distinguish each lesion from the others.
Seventeen children (mean age 9.0 ± 4.7 years), who had been referred for epilepsy associated with a brain tumor and operated, were selected. Preoperative MRI examinations were performed on a 1.5 T system and included anatomical images [T2-weighted, fluid-attenuated inversion recovery (FLAIR) and T1 pre- and post-injection images] as well as DWI and MRS [echo time (TE) = 30 and 135 ms]. Apparent diffusion coefficient (ADC) values were calculated in the lesion and healthy control. MRS relative quantification consisted in normalizing each metabolite by the sum (S) of all metabolites (S(TE=135 ms) = NAA+Cr+Cho; S(TE=30 ms) = NAA+Cr+Cho+Glx+mI). Univariate and multivariate analyses were performed in order to determine which criteria could differentiate the different epileptogenic brain lesions.
When taken alone, none of the MRI parameters was able to distinguish each disease from the others. Conventional MRI failed classifying two patients. When adding ADC to the linear discriminant analysis (LDA), one patient was still misclassified. Complete separation of the three groups was possible when combining conventional MRI, diffusion, and MRS either at long or short TE.
This study shows the added-value of multimodal MRI and MRS in the presurgical diagnosis of epileptogenic brain lesions in children.
Child s Nervous System 02/2012; 28(2):273-82. · 1.54 Impact Factor
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ABSTRACT: Cerebral stroke is a worldwide leading cause of disability. The two-pore domain K(+) channels identified as background channels are involved in many functions in brain under physiological and pathological conditions. We addressed the hypothesis that TRAAK, a mechano-gated and lipid-sensitive two-pore domain K(+) channel, is involved in the pathophysiology of brain ischemia. We studied the effects of TRAAK deletion on brain morphology and metabolism under physiological conditions, and during temporary focal cerebral ischemia in Traak(-/-) mice using a combination of in vivo magnetic resonance imaging (MRI) techniques and multinuclear magnetic resonance spectroscopy (MRS) methods. We provide the first in vivo evidence establishing a link between TRAAK and neurometabolism. Under physiological conditions, Traak(-/-) mice showed a particular metabolic phenotype characterized by higher levels of taurine and myo-inositol than Traak(+/+) mice. Upon ischemia, Traak(-/-) mice had a smaller infarcted volume, with lower contribution of cellular edema than Traak(+/+) mice. Moreover, brain microcirculation was less damaged, and brain metabolism and pH were preserved. Our results show that expression of TRAAK strongly influences tissue levels of organic osmolytes. Traak(-/-) mice resilience to cellular edema under ischemia appears related to their physiologically high levels of myo-inositol and of taurine, an aminoacid involved in the modulation of mitochondrial activity and cell death. The beneficial effects of TRAAK deletion designate this channel as a promising pharmacological target for the treatment against stroke.
PLoS ONE 01/2012; 7(12):e53266. · 4.09 Impact Factor
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ABSTRACT: We demonstrate for the first time the ability to determine in vivo and in utero the transitions between the main stages of white matter (WM) maturation in normal human fetuses using magnetic resonance diffusion tensor imaging (DTI) tractography. Biophysical characteristics of water motion are used as an indirect probe to evaluate progression of the tissue matrix organization in cortico-spinal tracts (CSTs), optic radiations (OR), and corpus callosum (CC) in 17 normal human fetuses explored between 23 and 38 weeks of gestation (GW) and selected strictly on minimal motion artifacts. Nonlinear polynomial (third order) curve fittings of normalized longitudinal and radial water diffusivities (Z-scores) as a function of age identify three different phases of maturation with specific dynamics for each WM bundle type. These phases may correspond to distinct cellular events such as axonal organization, myelination gliosis, and myelination, previously reported by other groups on post-mortem fetuses using immunostaining methods. According to the DTI parameter dynamics, we suggest that myelination (phase 3) appears early in the CSTs, followed by the OR and by the CC, respectively. DTI tractography provides access to a better understanding of fetal WM maturation.
Brain and behavior. 11/2011; 1(2):95-108.
