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RANJEVA Marie-Pierre

MD PhD

mail@univ-amu.fr
tel : +33 4 91 38 ** **
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Current Research Interest and projects

Publications

2018

Journal Article


  • Agosta, F, Spinelli, EG & Filippi, M 2018, “Neuroimaging in amyotrophic lateral sclerosis: current and emerging uses”, Expert Review of Neurotherapeutics, vol. 18, no. 5, p. 395-406, viewed 14November,2018, .


  • Alruwaili, AR, Pannek, K, Coulthard, A, Henderson, R, Kurniawan, ND & McCombe, P 2018, “A combined tract-based spatial statistics and voxel-based morphometry study of the first MRI scan after diagnosis of amyotrophic lateral sclerosis with subgroup analysis”, Journal of Neuroradiology, vol. 45, no. 1, p. 41-48, viewed 14November,2018, .
    Résumé : Background and purpose. – This study aims to compare the cortical and subcortical deep gray matter (GM) and white matter (WM) of ALS subjects and controls and to compare ALS subjects with (ALScog) and without (ALSnon-cog) cognitive impairment. Materials and methods. – The study was performed in 30 ALS subjects, and 19 healthy controls. Structural T1- and diffusion-weighted MRI data were analyzed using voxel-based morphometry (VBM) and tractbased spatial statistics (TBSS). Results. – All DTI measures and GM volume differed significantly between ALS subjects and controls. Compared to controls, greater DTI changes were present in ALScog than ALSnon-cog subjects. GM results showed reduction in the caudate nucleus volume in ALScog subjects compared to ALSnon-cog. and comparing all ALS with controls, there were changes on the right side and in a small region in the left middle frontal gyrus. Conclusion. – This combined DTI and VBM study showed changes in motor and extra-motor regions. The DTI changes were more extensive in ALScog than ALSnon-cog subjects. It is likely that the inclusion of ALS subjects with cognitive impairment in previous studies resulted in extra-motor WM abnormalities being reported in ALS subjects.


  • Bai, R, Springer, CS, Plenz, D & Basser, PJ 2018, “Fast, Na <sup>+</sup> /K <sup>+</sup> pump driven, steady-state transcytolemmal water exchange in neuronal tissue: A study of rat brain cortical cultures: Active Transcytolemmal Water Exchange in Neuronal Tissue”, Magnetic Resonance in Medicine, vol. 79, no. 6, p. 3207-3217, viewed 14November,2018, .
    Résumé : Purpose: Water homeostasis and transport play important roles in brain function (e.g., ion homeostasis, neuronal excitability, cell volume regulation, etc.). However, specific mechanisms of water transport across cell membranes in neuronal tissue have not been completely elaborated. Methods: The kinetics of transcytolemmal water exchange were measured in neuronal tissue using simultaneous, realtime fluorescence and nuclear magnetic resonance (NMR) measurements of perfused, active brain organotypic cortical cultures. Perfusion with a paramagnetic MRI contrast agent, gadoteridol, allows NMR determination of the unidirectional rate constant for steady-state cellular water efflux (kio), and the mole fraction of intracellular water (pi), related to the average cell volume (V). Changes in intracellular calcium concentration ½Ca2i þŠ were used as a proxy for neuronal activity and were monitored by fluorescence imaging. Results: The kio value, averaged over all cultures (N ¼ 99) at baseline, was 2.02 (61.72) sÀ1, indicating that on average, the equivalent of the entire intracellular water volume turns over twice each second. To probe possible molecular pathways, the specific Naþ-Kþ-ATPase (NKA) inhibitor, ouabain (1 mM), was transiently introduced into the perfusate. This caused significant transient changes (N ¼ 8): ½Ca2i þŠ rose $250%, V rose $89%, and kio fell $45%, with a metabolically active kio contribution probably eliminated by ouabain saturation. Conclusions: These results suggest that transcytolemmal water exchange in neuronal tissue involves mechanisms affected by NKA activity as well as passive pathways. The active pathway may account for half of the basal homeostatic water flux. Magn Reson Med 79:3207–3217, 2018. VC 2017 International Society for Magnetic Resonance in Medicine.

  • Bandt, SK, de Rochefort, L, Chen, W, Dimov, AV, Spincemaille, P, Kopell, BH, Gupta, A & Wang, Y 2018, “Clinical Integration of Quantitative Susceptibility Mapping (QSM) MRI into Neurosurgical Practice”, World Neurosurgery.
    Résumé : Quantitative susceptibility mapping (QSM), a recently developed magnetic resonance imaging technique, is introduced to the field of neurosurgery. A brief overview of the physics behind the technique is provided for a neurosurgical audience. QSM is unique in its ability to offer a quantitative assessment of tissue magnetic susceptibility source, which has only been detected as a blooming artifact in gradient echo acquisition. Standard susceptibility weighted imaging cannot localize nor quantify susceptibility source. Clinical applications of QSM are wide-reaching and include precise localization of the deep nuclei for deep brain stimulation electrode placement, differentiation between blood products and calcification within brain lesions to optimize intra-operative preparedness during resection, and enhanced sensitivity of cerebral micrometastasis identification. QSM can be obtained in all patients able to undergo magnetic resonance imaging and is integratable into busy neuroradiology programs. Examples are provided for QSM's clinical applications in neurosurgical care. Clinical integration of QSM may help clinicians better identify and characterize neurosurgical lesions thereby improving patient care.
    Mots-clés : advanced imaging techniques, crmbm, cvs, deep brain stimulation, glioma, meningioma, neuro-oncology, Quantitative Susceptibility Mapping, stereotactic navigation.

  • Béchir, N, Pecchi, É, Vilmen, C, Bernard, M, Bendahan, D & Giannesini, B 2018, “ActRIIB blockade does not limit ATP supply in mouse skeletal muscle in vivo”, Muscle & Nerve.
    Résumé : INTRODUCTION: Postnatal activin/myostatin type IIB receptor (ActRIIB) blockade increases skeletal muscle mass and strength, but also increases muscle fatigability and impairs oxidative metabolism. The aim of this study was to determine in vivo whether this increased fatigability is due to energy supply limitation. METHODS: The impact of 8-week ActRIIB blockade with soluble receptor (sActRIIB-Fc) upon muscle function and ATP fluxes was investigated noninvasively using multimodal magnetic resonance and indirect calorimetry measurements in wild-type mice. RESULTS: ActRIIB blockade reduced (-41%) the muscle apparent mitochondrial capacity and increased (+11%) the basal body energy expenditure. During a fatiguing exercise, ActRIIB blockade decreased both oxidative ATP production rate (-32%) and fatigue resistance (-36%) but these changes affected neither the total ATP production rate nor the contractile ATP cost. DISCUSSION: These findings demonstrate that the increased fatigability following ActRIIB blockade is not due to limitation in energy supply and/or disturbance in contractile ATP cost. This article is protected by copyright. All rights reserved.
    Mots-clés : Activin myostatin receptor, crmbm, Energy expenditure, Exercise, Fatigue, msk, Muscle wasting therapy, Oxidative capacity.


  • Beck, ES, Sati, P, Sethi, V, Kober, T, Dewey, B, Bhargava, P, Nair, G, Cortese, IC & Reich, DS 2018, “Improved Visualization of Cortical Lesions in Multiple Sclerosis Using 7T MP2RAGE”, American Journal of Neuroradiology, vol. 39, no. 3, p. 459-466, viewed 14November,2018, .
    Résumé : BACKGROUND AND PURPOSE: Cortical lesions are common and often extensive in multiple sclerosis but are difficult to visualize by MRI, leaving important questions about their clinical implications and response to therapy unanswered. Our aim was to determine whether cortical lesions are better visualized using magnetization prepared 2 rapid acquisition gradient echoes (MP2RAGE) than T2*-weighted imaging on 7T MR imaging. MATERIALS AND METHODS: Brain MR imaging using T1-weighted MP2RAGE at 500-␮m isotropic resolution, T2*-weighted gradient-echo, and T2*-weighted segmented echo-planar imaging sequences were collected for 13 patients with MS and 5 age-matched neurologically healthy controls on a 7T research system. One MS case underwent postmortem MR imaging including gradient-echo and MP2RAGE sequences, after which cortical lesions seen on MR imaging were assessed with immunohistochemistry. RESULTS: MP2RAGE detected 203 cortical lesions (median, 16 lesions/case; interquartile range, 15), compared to 92 with T2*gradient-echo (median, 7; interquartile range, 8; P Ͻ .001) and 81 with T2*EPI (median, 7; interquartile range, 5; P Ͻ .001). This increase in lesion number detected on MP2RAGE versus T2* was observed for juxtacortical, leukocortical, and intracortical lesions. Forty-three percent of all cortical lesions were identified only on MP2RAGE. White matter lesion volume correlated with total juxtacortical (r ϭ 0.86, P Ͻ .001) and leukocortical lesion volume (r ϭ 0.70, P Ͻ .01) but not intracortical lesion volume, suggesting that pathophysiology may differ by lesion type. Of 4 suspected lesions seen on postmortem imaging, 3 were found to be true cortical lesions while 1 represented postmortem tissue damage. CONCLUSIONS: A combination of MP2RAGE and T2*-weighted imaging at 7T improved detection of cortical lesions and should enable longitudinal studies to elucidate their spatiotemporal dynamics and clinical implications.

  • Benacchio, S, Doutres, O, Le Troter, A, Varoquaux, A, Wagnac, E, Callot, V & Sgard, F 2018, “Estimation of the ear canal displacement field due to in-ear device insertion using a registration method on a human-like artificial ear”, Hearing Research, vol. 365, p. 16-27.
    Résumé : Passive and active in-ear devices (IED) occluding the ear canal are commonly used to (i) protect people from high noise levels (earplugs), (ii) assist people suffering from hearing impairment (hearing aids) or (iii) help people in listening from their sound systems (earbuds). However, the usability and/or efficiency of IEDs can be greatly affected by several discomfort components (physical, acoustical and functional). The mechanical pressure exerted by the IED onto the ear canal walls is greatly suspected to affect the aforementioned comfort components. This physical characteristic is closely related to the displacement field induced by the IED insertion, which has to be known for a better understanding of perceived discomfort. Thus, this paper proposes to validate a method based on medical images to estimate the displacement field of the ear canal walls due to the insertion of an IED. The approach is validated on a human-like artificial ear with canal geometry deformed using two custom molded IEDs with controlled shapes. These geometries are obtained using computed tomography imaging and the displacement field is computed using a registration method. The errors due to the ear canal segmentation and to the registration steps are small enough to compute a relevant estimation of the expected displacement field. Results show that the amplitude of the displacement and its location into the ear canal can be evaluated with an accuracy of ± 0.2 mm and ± 0.4 mm respectively. Preliminary results on images with a degraded resolution indicate that the proposed approach used to assess the displacement field of the ear canal walls using computed tomography images could be applied on magnetic resonance images, which is a preferred method to image human subject ear canals for future investigations.
    Mots-clés : crmbm, Deformation, Displacement, Ear canal, Earbud, Earplug, Hearing aids, snc.

  • Bentatou, Z, Finas, M, Habert, P, Kober, F, Guye, M, Bricq, S, Lalande, A, Frandon, J, Dacher, JN, Dubourg, B, Habib, G, Caudron, J, Normant, S, Rapacchi, S, Bernard, M & Jacquier, A 2018, “Distribution of left ventricular trabeculation across age and gender in 140 healthy Caucasian subjects on MR imaging”, Diagnostic and Interventional Imaging.
    Résumé : PURPOSE: The purpose of this study was to quantify the distribution of trabeculated (T) and compact (C) left ventricular (LV) myocardium masses in a healthy Caucasian population against age, gender and LV parameters, and to provide normal values for T, C and T/C. MATERIALS AND METHODS: One hundred and forty healthy subjects were prospectively recruited and underwent cardiac MRI at 1.5T with a stack of short-axis cine sequences covering the entire LV. End-diastolic volume (EDV), C and T masses were quantified using a semi-automatic method. Ejection fraction (EF) and T/C ratio were computed. RESULTS: We included 70 men and 70 women with a mean age of 44±14 (SD) years (range: 20-69 years). The mean EF was 63.7±6.3 (SD) % (range: 50.7-82.0%), the mean EDV was 75.9±16.2 (SD) mL/m2 (range: 36.4-112.2mL/m2), the mean C mass was 53.9±11.2 (SD) g/m2 (range: 26.5-93.4g/m2) and the mean T mass was 4.9±2.4 (SD) g/m2 (range: 1.1-11.4g/m2). The T/C ratio was 9.2±4.5% (range: 2.0-29.4%). Multivariate ANOVA test showed that the compact mass was influenced by EDV (P<0.0001), EF (P=0.001) and gender (P<0.0001), and the trabeculated mass depended on EDV (P<0.0001), gender (P=0.002) and age (P<0.0001), while the T/C ratio was only influenced by age (P=0.0003). Spearman test showed a correlation between EDV and C (r=0.60; P<0.0001),T (r=0.46; P<0.0001) and T/C ratio (r=0.26; P=0.0023).T and T/C ratio correlated with EF (r=-0.18, P=0.0373; r=-0.18, P=0.0321, respectively). CONCLUSION: While the compact and trabeculated myocardium masses appear to relate separately to the cardiac function, age and gender, their ratio T/C appears to only decrease with age. Furthermore, we propose here normal values for T, C and T/C in a cohort of healthy Caucasians subjects.
    Mots-clés : Cardiac magnetic resonance imaging (CMR), crmbm, cvs, Left ventricular function, Left ventricular remodeling, Myocardium.

  • Benzaquen, M, Flachaire, B, Rouby, F, Berbis, P & Guis, S 2018, “Paradoxical pustular psoriasis induced by ustekinumab in a patient with Crohn's disease-associated spondyloarthropathy”, Rheumatology International.
    Résumé : Palmoplantar pustular psoriasis (PPP) is a clinical form of psoriasis, for which tumor necrosis factor alpha inhibitors (TNFi) or interleukins 12/23 inhibitor (ustekinumab) can be a therapeutic option. Paradoxical psoriatic reactions induced by TNFi are now well known. We present the exceptional case of a paradoxical PPP appeared under ustekinumab in a patient with Crohn's disease-associated spondyloarthropathy. A 58-year-old woman presented with recent peripheral inflammatory arthralgias appeared in the context of a Crohn's disease diagnosed in 2008. Three weeks after the first injection of ustekinumab 390 mg for a refractory Crohn's disease, a slight pruritic erythematous and pustular dermatosis appeared on the right hand palm. The clinical aspect was strongly in favor of a PPP. Ustekinumab was discontinued and replaced by golimumab, leading to a complete healing of PPP after 15 days of discontinuation. Causality assessment calculated using the French method was plausible for ustekinumab in the induction of PPP. It was based on a compatible chronology according to time to onset associated with complete recovery 2 weeks after cessation of treatment, and on the negative assessment of an alternative etiology (nor bacterial or viral infection, nor other treatment taken by the patient, nor previous history of psoriasis). The worsening of underlying psoriasis under ustekinumab through the appearance of generalized or palmoplantar pustules has already been reported in five cases. We describe to our knowledge the first case of paradoxical PPP under ustekinumab in a patient with no known underlying psoriasis.
    Mots-clés : Crohn’s disease, msk, Paradoxical, Pustular psoriasis, Spondyloarthropathy, Ustekinumab.

  • Berg, OK, Kwon, OS, Hureau, TJ, Clifton, HL, Thurston, T, Le Fur, Y, Jeong, E-K, Amann, M, Richardson, RS, Trinity, JD, Wang, E & Layec, G 2018, “Maximal strength training increases muscle force generating capacity and the anaerobic ATP synthesis flux without altering the cost of contraction in elderly”, Experimental Gerontology, vol. 111, p. 154-161.
    Résumé : Aging is associated with a progressive decline in skeletal muscle function, then leading to impaired exercise tolerance. Maximal strength training (MST) appears to be a practical and effective intervention to increase both exercise capacity and efficiency. However, the underlying physiological mechanisms responsible for these functional improvements are still unclear. Accordingly, the purpose of this study was to examine the intramuscular and metabolic adaptations induced by 8 weeks of knee-extension MST in the quadriceps of 10 older individuals (75 ± 9 yrs) by employing a combination of molecular, magnetic resonance 1H-imaging and 31P-spectroscopy, muscle biopsies, motor nerve stimulation, and indirect calorimetry techniques. Dynamic and isometric muscle strength were both significantly increased by MST. The greater torque-time integral during sustained isometric maximal contraction post-MST (P = 0.002) was associated with increased rates of ATP synthesis from anaerobic glycolysis (PRE: 10 ± 7 mM·min-1; POST: 14 ± 7 mM·min-1, P = 0.02) and creatine kinase reaction (PRE: 31 ± 10 mM·min-1; POST: 41 ± 10 mM·min-1, P = 0.006) such that the ATP cost of contraction was not significantly altered. Expression of fast myosin heavy chain, quadriceps muscle volume, and submaximal cycling net efficiency were also increased with MST (P = 0.005; P = 0.03 and P = 0.03, respectively). Overall, MST induced a shift toward a more glycolytic muscle phenotype allowing for greater muscle force production during sustained maximal contraction. Consequently, some of the MST-induced improvements in exercise tolerance might stem from a greater anaerobic capacity to generate ATP, while the improvement in exercise efficiency appears to be independent from an alteration in the ATP cost of contraction.
    Mots-clés : (31)P-MRS, Aging, ATP cost of contraction, Energetic properties, Glycolysis, msk, Strength training.

  • Bydder, M, Zaaraoui, W, Ridley, B, Soubrier, M, Bertinetti, M, Confort-Gouny, S, Schad, L, Guye, M & Ranjeva, J-P 2018, “Dynamic 23Na MRI - A non-invasive window on neuroglial-vascular mechanisms underlying brain function”, NeuroImage.
    Résumé : A novel magnetic resonance imaging (MRI) acquisition and reconstruction method for obtaining a series of dynamic sodium 23Na-MRI acquisitions was designed to non-invasively assess the signal variations of brain sodium during a hand motor task in 14 healthy human volunteers on an ultra high field (7T) MR scanner. Regions undergoing activation and deactivation were identified with reference to conventional task-related BOLD functional MRI (fMRI). Activation observed in the left central regions, the supplementary motor areas and the left cerebellum induced an increase in the sodium signal observed at ultra short echo time and a decrease in the 23Na signal observed at long echo time. Based on a simple model of two distinct sodium pools (namely, restricted and mobile sodium), the ultra short echo time measures the totality of sodium whereas the long echo time is mainly sensitive to mobile sodium. This activation pattern is consistent with previously described processes related to an influx of Na+ into the intracellular compartments and a moderate increase in the cerebral blood volume (CBV). In contrast, deactivation observed in the right central regions ipsilateral to the movement, the precuneus and the left cerebellum induced a slight decrease in sodium signal at ultra short echo time and an increase of sodium signal at longer echo times. This inhibitory pattern is compatible with a slight decrease in CBV and an efflux of intracellular Na+ to the extracellular compartments that may reflect neural dendritic spine and astrocytic shrinkage, and an increase of sodium in the extracellular fraction. In conclusion, cerebral dynamic 23Na MRI experiments can provide access to the ionic transients following a functional task occurring within the neuro-glial-vascular ensemble. This has the potential to open up a novel non-invasive window on the mechanisms underlying brain function.
    Mots-clés : (23)Na MRI, 7T, Brain, crmbm, Excitation, fMRI, Inhibition, Motor system, snc, Sodium.

  • Chatel, B, Messonnier, LA, Barge, Q, Vilmen, C, Noirez, P, Bernard, M, Pialoux, V & Bendahan, D 2018, “Endurance training reduces exercise-induced acidosis and improves muscle function in a mouse model of sickle cell disease”, Molecular Genetics and Metabolism, vol. 123, no. 3, p. 400-410.
    Résumé : Sickle cell disease (SCD) mice (Townes model of SCD) presented exacerbated exercise-induced acidosis and fatigability as compared to control animals. We hypothesize that endurance training could represent a valuable approach to reverse these muscle defects. Endurance-trained HbAA (HbAA-END, n=10), HbAS (HbAS-END, n=11) and HbSS (HbSS-END, n=8) mice were compared to their sedentary counterparts (10 HbAA-SED, 10 HbAS-SED and 9 HbSS-SED mice) during two rest - exercise - recovery protocols during which muscle energetics and function were measured. In vitro analyses of some proteins involved in muscle energetics, pH regulation and oxidative stress were also performed. Exercise-induced acidosis was lower in HbSS-END mice as compared to their sedentary counterparts during both moderate (p<0.001) and intense (p<0.1) protocols. The total force production measured during both protocols was higher in trained mice compared to sedentary animals. In vitro analyses revealed that enolase/citrate synthase ratio was reduced in HbSS-END (p<0.001) and HbAS-END (p<0.01) mice compared to their sedentary counterparts. In addition, malondialdehyde concentration was reduced in trained mice (p<0.05). In conclusion, endurance training would reverse the more pronounced exercise-induced acidosis, reduce oxidative stress and ameliorate some of the muscle function parameters in SCD mice.
    Mots-clés : crmbm, msk, Muscle energetics, Muscle force production, pH, Physical activity.

  • Chatel, B, Messonnier, LA & Bendahan, D 2018, “Do we have to consider acidosis induced by exercise as deleterious in sickle cell disease?”, Experimental Physiology.
    Résumé : Sickle cell disease (SCD) is an inherited haemoglobin (Hb) disorder and the most common monogenic disease in the world. The root cause of this pathology is the synthesis of an abnormal Hb (HbS) that polymerizes in deoxygenated conditions, leading to the sickling of red blood cells (RBC). Acidosis is well-recognized as a promoter of HbS polymerisation, and thereby RBC sickling. Indeed, it has been shown in vitro that the relative amount of sickled RBC increased markedly from 1% at pH 7.4 to more than 90% at pH 7.0. Nevertheless, no study has directly tested if exercise-induced acidosis could favour SCD complications. Yet, increased knowledge of the effects of metabolic acidosis during exercise could be of importance given the conclusions reached in several studies that proposed regular physical exercise as a therapeutic strategy in managing SCD. In this review, we discuss the potential consequences of exercise-induced acidosis on the pathophysiology of SCD. We also propose some potential therapeutic interventions aiming at reducing the metabolic acidosis related to exercise. This article is protected by copyright. All rights reserved.
    Mots-clés : crmbm, exercise therapy, msk, pH, Sickle cell anaemia, vaso-occlusive crisis.

  • Chatel, B, Messonnier, LA, Vilmen, C, Bernard, M, Pialoux, V & Bendahan, D 2018, “Exacerbated metabolic changes in skeletal muscle of sickle cell mice submitted to an acute ischemia - reperfusion paradigm”, Clinical Science (London, England: 1979).
    Résumé : Sickle cell disease (SCD) is characterized by painful vaso-occlusive crises. While there are several metabolic abnormalities potentially associated with muscular ischemia - reperfusion cycles which could be harmful in the context of SCD, the metabolic consequences of such events are still unknown. Ten controls (HbAA), 13 heterozygous (HbAS) and 10 homozygous (HbSS) SCD mice were submitted to a standardized protocol of rest - ischemia - reperfusion of the right leg during which ATP, phosphocreatine and inorganic phosphate concentrations as well as intramuscular pH were measured using phosphorous magnetic resonance spectroscopy (MRS). Forty-eight hours later, skeletal muscles were harvested. Oxidative stress markers were then measured on the tibialis anterior At the end of the ischemic period, HbSS mice had a lower pH value as compared to the HbAA (p < 0.01) and HbAS groups (p < 0.01). During the reperfusion period, the initial rate of phosphocreatine resynthesis was lower in HbSS mice compared to HbAA (p < 0.05) and HbAS (p < 0.01) animals. No significant difference among groups was observed regarding oxidative stress markers. HbSS mice displayed a higher intramuscular acidosis during the ischemic period while their mitochondrial function was impaired as compared to their HbAA and HbAS counterparts. These metabolic abnormalities could worsen the complications related to the pathology of SCD.
    Mots-clés : Acidosis, crmbm, Mitochondrial function, msk, Skeletal muscle energetics, Vaso-occlusive crisis.

  • Choquet, C, Nguyen, THM, Sicard, P, Buttigieg, E, Tran, TT, Kober, F, Varlet, I, Sturny, R, Costa, MW, Harvey, RP, Nguyen, C, Rihet, P, Richard, S, Bernard, M, Kelly, RG, Lalevée, N & Miquerol, L 2018, “Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy”, PLoS genetics, vol. 14, no. 7, p. e1007502.
    Résumé : Left ventricular non-compaction (LVNC) is a rare cardiomyopathy associated with a hypertrabeculated phenotype and a large spectrum of symptoms. It is still unclear whether LVNC results from a defect of ventricular trabeculae development and the mechanistic basis that underlies the varying severity of this pathology is unknown. To investigate these issues, we inactivated the cardiac transcription factor Nkx2-5 in trabecular myocardium at different stages of trabecular morphogenesis using an inducible Cx40-creERT2 allele. Conditional deletion of Nkx2-5 at embryonic stages, during trabecular formation, provokes a severe hypertrabeculated phenotype associated with subendocardial fibrosis and Purkinje fiber hypoplasia. A milder phenotype was observed after Nkx2-5 deletion at fetal stages, during trabecular compaction. A longitudinal study of cardiac function in adult Nkx2-5 conditional mutant mice demonstrates that excessive trabeculation is associated with complex ventricular conduction defects, progressively leading to strain defects, and, in 50% of mutant mice, to heart failure. Progressive impaired cardiac function correlates with conduction and strain defects independently of the degree of hypertrabeculation. Transcriptomic analysis of molecular pathways reflects myocardial remodeling with a larger number of differentially expressed genes in the severe versus mild phenotype and identifies Six1 as being upregulated in hypertrabeculated hearts. Our results provide insights into the etiology of LVNC and link its pathogenicity with compromised trabecular development including compaction defects and ventricular conduction system hypoplasia.
    Mots-clés : crmbm, cvs.

  • Cignetti, F, Vaugoyeau, M, Decker, LM, Grosbras, M-H, Girard, N, Chaix, Y, Péran, P & Assaiante, C 2018, “Brain network connectivity associated with anticipatory postural control in children and adults”, Cortex; a Journal Devoted to the Study of the Nervous System and Behavior, vol. 108, p. 210-221.
    Résumé : Internal models provide a coherent framework for understanding motor behavior. Examples for the use of internal models include anticipatory postural adjustments (APAs), where the individual anticipates and cancels out the destabilizing effect of movement on body posture. Yet little is known about the functional changes in the brain supporting the development of APAs. Here, we addressed this issue by relating individual differences in APAs as assessed during bimanual load lifting to interindividual variation in brain network interactions at rest. We showed that the strength of the connectivity between three main canonical brain networks, namely the cingulo-opercular, the fronto-parietal and the somatosensory-motor networks, is an index of the ability to implement APAs from late childhood (9- to 11-year-old children). We also found an effect of age on the relationship between APAs and coupling strength between these networks, consistent with the notion that APAs are near but not yet fully mature in children. We discuss the implications of these findings for our understanding of learning disorders with impairment in predictive motor control.
    Mots-clés : Anticipatory postural adjustments, Brain networks, Brain-behavior relationship, Development, Functional connectivity, snc.

  • Ciron, J, Audoin, B, Bourre, B, Brassat, D, Durand-Dubief, F, Laplaud, D, Maillart, E, Papeix, C, Vukusic, S, Zephir, H, Marignier, R, Collongues, N & NOMADMUS group, under the aegis of OFSEP, SFSEP, 2018, “Recommendations for the use of Rituximab in neuromyelitis optica spectrum disorders”, Revue Neurologique, vol. 174, no. 4, p. 255-264.
    Résumé : There is growing evidence of a preventive effect of Rituximab (RTX) in neuromyelitis optica spectrum disorders (NMO-SD). This monoclonal antibody against CD20 is becoming the most widely used preventive therapy in NMO-SD, as a first-line therapy or as a rescue therapy. Nevertheless, considerable heterogeneity still exists concerning the pre-treatment work-up, the vaccinations required before and under treatment, the number and dosage of infusions, prevention of the risk of infusion-related reactions, prevention of infections under treatment, and frequency of therapeutic cycles. Thanks to a collaborative work among NMO-SD experts belonging to the NOMADMUS project, we provide here recommendations for all these topics concerning RTX use in NMO-SD.
    Mots-clés : Guidelines, Neuromyelitis optica, Recommendations, Rituximab, snc, Treatment.

  • Combès, B, Kerbrat, A, Ferré, JC, Callot, V, Maranzano, J, Badji, A, Le Page, E, Labauge, P, Ayrignac, X, Carra Dallière, C, de Champfleur, NM, Pelletier, J, Maarouf, A, de Seze, J, Collongues, N, Brassat, D, Durand-Dubief, F, Barillot, C, Bannier, E, Edan, G & EMISEP Study Group, 2018, “Focal and diffuse cervical spinal cord damage in patients with early relapsing-remitting MS: A multicentre magnetisation transfer ratio study”, Multiple Sclerosis (Houndmills, Basingstoke, England), p. 1352458518781999.
    Résumé : BACKGROUND: Studies including patients with well-established multiple sclerosis (MS) have shown a significant and disability-related reduction in the cervical spinal cord (SC) magnetisation transfer ratio (MTR). OBJECTIVES: The objectives are to (1) assess whether MTR reduction is already measurable in the SC of patients with early relapsing-remitting multiple sclerosis (RRMS) and (2) describe its spatial distribution. METHODS: We included 60 patients with RRMS <12  months and 34 age-matched controls at five centres. Axial T2*w, sagittal T2w, sagittal phase-sensitive inversion recovery (PSIR), 3DT1w, and axial magnetisation transfer (MT) images were acquired from C1 to C7. Lesions were manually labelled and mean MTR values computed both for the whole SC and for normal-appearing SC in different regions of interest. RESULTS: Mean whole SC MTR was significantly lower in patients than controls (33.7 vs 34.9  pu, p  =  0.00005), even after excluding lesions (33.9  pu, p  =  0.0003). We observed a greater mean reduction in MTR for vertebral levels displaying the highest lesion loads (C2-C4). In the axial plane, we observed a greater mean MTR reduction at the SC periphery and barycentre. CONCLUSION: Cervical SC tissue damage measured using MTR is not restricted to macroscopic lesions in patients with early RRMS and is not homogeneously distributed.
    Mots-clés : crmbm, magnetisation transfer imaging, Quantitative MRI, relapsing–remitting multiple sclerosis, snc, Spinal cord.

  • Combès, B, Monteau, L, Bannier, E, Callot, V, Labauge, P, Ayrignac, X, Carra Dallière, C, Pelletier, J, Maarouf, A, de Seze, J, Collongues, N, Barillot, C, Edan, G, Ferré, JC, Kerbrat, A & EMISEP study group, 2018, “Measurement of magnetization transfer ratio (MTR) from cervical spinal cord: Multicenter reproducibility and variability”, Journal of magnetic resonance imaging: JMRI.
    Résumé : BACKGROUND: Assessing the multicenter variability of magnetization transfer ratio (MTR) measurements in the spinal cord of healthy controls is the first step toward investigating its clinical use as a biomarker. PURPOSE: To analyze the between-session, between-participant, and between-scanner variability of MTR measurements in automatically extracted regions of interest in the cervical cord of healthy controls. STUDY TYPE: Control study. POPULATION: Forty-four participants, distributed across five MRI scanners (all from the same manufacturer). Ten participants were scanned twice in the same scanner, and 10 others were scanned twice in two different scanners. FIELD STRENGTH/SEQUENCE: 3D-gradient echo images, centered on C5, without and with magnetization transfer prepulse at 3T. ASSESSMENT: We calculated the mean MTR for different vertebral levels in the whole cord (WC), as well as in the white matter and gray matter, and determined the between-session, between-participant, and between-scanner variabilities. STATISTICAL TESTS: Coefficients of variation and intraclass correlations (ICCs) for the different variabilities and their associated confidence intervals. RESULTS: The MTR measurements for Levels C4-C6 (near the slab center) exhibited a mean value in WC of 34.6 pu and a pooled standard deviation of 0.9 pu. The between-session coefficient of variation was estimated as 2.3% (ICC = 0.63), the between-participant coefficient as 1.6% (ICC = 0.32), and the between-scanner coefficient as 0.7% (ICC = 0.05). The resulting aggregate coefficient of variation was 2.9%, which was sufficiently low to detect an MTR reduction of 1 pu between groups of about 45 participants (Type-I error rate: 0.05; Type-II error rate: 0.10). DATA CONCLUSION: The good between-scanner reproducibility and low overall variability in cervical spinal cord MTR measurements in a control population might pave the way for multicenter analyses in various neurological diseases with moderate cohort sizes. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018.
    Mots-clés : crmbm, MTR, multicenter, quantitative MRI, reproducibility, snc, spinal cord.

  • De Leener, B, Fonov, VS, Collins, DL, Callot, V, Stikov, N & Cohen-Adad, J 2018, “PAM50: Unbiased multimodal template of the brainstem and spinal cord aligned with the ICBM152 space”, NeuroImage, vol. 165, p. 170-179.
    Résumé : Template-based analysis of multi-parametric MRI data of the spinal cord sets the foundation for standardization and reproducibility, thereby helping the discovery of new biomarkers of spinal-related diseases. While MRI templates of the spinal cord have been recently introduced, none of them cover the entire spinal cord. In this study, we introduced an unbiased multimodal MRI template of the spinal cord and the brainstem, called PAM50, which is anatomically compatible with the ICBM152 brain template and uses the same coordinate system. The PAM50 template is based on 50 healthy subjects, covers the full spinal cord (C1 to L2 vertebral levels) and the brainstem, is available for T1-, T2-and T2*-weighted MRI contrasts and includes a probabilistic atlas of the gray matter and white matter tracts. Template creation accuracy was assessed by computing the mean and maximum distance error between each individual spinal cord centerline and the PAM50 centerline, after registration to the template. Results showed high accuracy for both T1- (mean = 0.37 ± 0.06 mm; max = 1.39 ± 0.58 mm) and T2-weighted (mean = 0.11 ± 0.03 mm; max = 0.71 ± 0.27 mm) contrasts. Additionally, the preservation of the spinal cord topology during the template creation process was verified by comparing the cross-sectional area (CSA) profile, averaged over all subjects, and the CSA profile of the PAM50 template. The fusion of the PAM50 and ICBM152 templates will facilitate group and multi-center studies of combined brain and spinal cord MRI, and enable the use of existing atlases of the brainstem compatible with the ICBM space.
    Mots-clés : Atlas, crmbm, ICBM, MRI, Spinal cord, Template.

  • Durozard, P, Maarouf, A, Boutiere, C, Ruet, A, Brochet, B, Vukusic, S, Carra-Dalliere, C, Labauge, P, Mathey, G, Debouverie, M, Papeix, C, Maillart, E, Lubetzki, C, Bensa, C, Gout, O, Giannesini, C, Stankoff, B, Ciron, J, Brassat, D, Pelletier, J, Rico Lamy, A, Audoin, B & SFSEP and OFSEP groups, 2018, “Efficacy of rituximab in refractory RRMS”, Multiple Sclerosis (Houndmills, Basingstoke, England), p. 1352458518772748.
    Résumé : OBJECTIVE: To investigate the efficacy of rituximab as rescue therapy in patients with relapsing-remitting multiple sclerosis (RRMS) and persistent disease activity confirmed by magnetic resonance imaging (MRI) despite immunosuppressive disease-modifying therapy (DMT). METHODS: In this observational nationwide retrospective multicenter study, we first identified 351 off-label rituximab-treated patients through a cohort of 15,984 RRMS patients. In this group, we identified patients with disease activity prior to rituximab confirmed by MRI (one or more new T2 lesion and/or gadolinium-enhancing lesion) despite immunosuppressive DMT (fingolimod, natalizumab, or mitoxantrone) with a follow-up after rituximab initiation longer than 6 months. Outcome data were collected from the French Observatory of Multiple Sclerosis (OFSEP) register and medical charts. RESULTS: A total of 50 patients were identified. Median rituximab treatment duration was 1.1 (0.5-6.4) year. Mean annualized relapse rate significantly decreased from 0.8 during last immunosuppressive DMT to 0.18 after rituximab ( p < 0.0001). While 72% of patients showed gadolinium-enhancing lesions on the last MRI performed during last immunosuppressive DMT, 8% of them showed gadolinium-enhancing lesions on the first MRI performed 6.1 (range 1.4-18.4) months after rituximab ( p < 0.0001). CONCLUSION: This study provides level IV evidence that rituximab reduces clinical and MRI disease activity in patients with active RRMS despite immunosuppressive DMT.
    Mots-clés : disease-modifying therapies, Multiple sclerosis, relapsing/remitting, second-line treatment, snc, treatment response.

  • Fouré, A, Ogier, AC, Le Troter, A, Vilmen, C, Feiweier, T, Guye, M, Gondin, J, Besson, P & Bendahan, D 2018, “Diffusion Properties and 3D Architecture of Human Lower Leg Muscles Assessed with Ultra-High-Field-Strength Diffusion-Tensor MR Imaging and Tractography: Reproducibility and Sensitivity to Sex Difference and Intramuscular Variability”, Radiology, vol. 287, no. 2, p. 592-607.
    Résumé : Purpose To demonstrate the reproducibility of the diffusion properties and three-dimensional structural organization measurements of the lower leg muscles by using diffusion-tensor imaging (DTI) assessed with ultra-high-field-strength (7.0-T) magnetic resonance (MR) imaging and tractography of skeletal muscle fibers. On the basis of robust statistical mapping analyses, this study also aimed at determining the sensitivity of the measurements to sex difference and intramuscular variability. Materials and Methods All examinations were performed with ethical review board approval; written informed consent was obtained from all volunteers. Reproducibility of diffusion tensor indexes assessment including eigenvalues, mean diffusivity, and fractional anisotropy (FA) as well as muscle volume and architecture (ie, fiber length and pennation angle) were characterized in lower leg muscles (n = 8). Intramuscular variability and sex differences were characterized in young healthy men and women (n = 10 in each group). Student t test, statistical parametric mapping, correlation coefficients (Spearman rho and Pearson product-moment) and coefficient of variation (CV) were used for statistical data analysis. Results High reproducibility of measurements (mean CV ± standard deviation, 4.6% ± 3.8) was determined in diffusion properties and architectural parameters. Significant sex differences were detected in FA (4.2% in women for the entire lower leg; P = .001) and muscle volume (21.7% in men for the entire lower leg; P = .008), whereas architecture parameters were almost identical across sex. Additional differences were found independently of sex in diffusion properties and architecture along several muscles of the lower leg. Conclusion The high-spatial-resolution DTI assessed with 7.0-T MR imaging allows a reproducible assessment of structural organization of superficial and deep muscles, giving indirect information on muscle function. ©RSNA, 2018 Online supplemental material is available for this article.
    Mots-clés : crmbm, msk.

  • Fouré, A, Pini, L, Rappacchi, S, Ogier, AC, Mattei, J-C, Bydder, M, Guye, M & Bendahan, D 2018, “Ultrahigh-Field Multimodal MRI Assessment of Muscle Damage”, Journal of magnetic resonance imaging: JMRI.

  • Fournely, M, Petit, Y, Wagnac, É, Laurin, J, Callot, V & Arnoux, P-J 2018, “High-speed video analysis improves the accuracy of spinal cord compression measurement in a mouse contusion model”, Journal of Neuroscience Methods, vol. 293, p. 1-5.
    Résumé : BACKGROUND: Animal models of spinal cord injuries aim to utilize controlled and reproducible conditions. However, a literature review reveals that mouse contusion studies using equivalent protocols may show large disparities in the observed impact force vs. cord compression relationship. The overall purpose of this study was to investigate possible sources of bias in these measurements. The specific objective was to improve spinal cord compression measurements using a video-based setup to detect the impactor-spinal cord time-to-contact. NEW METHOD: A force-controlled 30kDyn unilateral contusion at C4 vertebral level was performed in six mice with the Infinite Horizon impactor (IH). High-speed video was used to determine the time-to-contact between the impactor tip and the spinal cord and to compute the related displacement of the tip into the tissue: the spinal cord compression and the compression ratio. RESULTS & COMPARISON WITH EXISTING METHOD(S): Delayed time-to-contact detection with the IH device led to an underestimation of the cord compression. Compression values indicated by the IH were 64% lower than those based on video analysis (0.33mm vs. 0.88mm). Consequently, the mean compression ratio derived from the device was underestimated when compared to the value derived from video analysis (22% vs. 61%). CONCLUSIONS: Default time-to-contact detection from the IH led to significant errors in spinal cord compression assessment. Accordingly, this may explain some of the reported data discrepancies in the literature. The proposed setup could be implemented by users of contusion devices to improve the quantative description of the primary injury inflicted to the spinal cord.
    Mots-clés : Compression ratio, Contusion device, crmbm, High-speed video analysis, Mouse model, snc, Spinal cord injury.

  • Frandon, J, Bricq, S, Bentatou, Z, Marcadet, L, Barral, PA, Finas, M, Fagret, D, Kober, F, Habib, G, Bernard, M, Lalande, A, Miquerol, L & Jacquier, A 2018, “Semi-automatic detection of myocardial trabeculation using cardiovascular magnetic resonance: correlation with histology and reproducibility in a mouse model of non-compaction”, Journal of Cardiovascular Magnetic Resonance: Official Journal of the Society for Cardiovascular Magnetic Resonance, vol. 20, no. 1, p. 70.
    Résumé : BACKGROUND: The definition of left ventricular (LV) non-compaction is controversial, and discriminating between normal and excessive LV trabeculation remains challenging. Our goal was to quantify LV trabeculation on cardiovascular magnetic resonance (CMR) images in a genetic mouse model of non-compaction using a dedicated semi-automatic software package and to compare our results to the histology used as a gold standard. METHODS: Adult mice with ventricular non-compaction were generated by conditional trabecular deletion of Nkx2-5. Thirteen mice (5 controls, 8 Nkx2-5 mutants) were included in the study. Cine CMR series were acquired in the mid LV short axis plane (resolution 0.086 × 0.086x1mm3) (11.75 T). In a sub set of 6 mice, 5 to 7 cine CMR were acquired in LV short axis to cover the whole LV with a lower resolution (0.172 × 0.172x1mm3). We used semi-automatic software to quantify the compacted mass (Mc), the trabeculated mass (Mt) and the percentage of trabeculation (Mt/Mc) on all cine acquisitions. After CMR all hearts were sliced along the short axis and stained with eosin, and histological LV contouring was performed manually, blinded from the CMR results, and Mt, Mc and Mt/Mc were quantified. Intra and interobserver reproducibility was evaluated by computing the intra class correlation coefficient (ICC). RESULTS: Whole heart acquisition showed no statistical significant difference between trabeculation measured at the basal, midventricular and apical parts of the LV. On the mid-LV cine CMR slice, the median Mt was 0.92 mg (range 0.07-2.56 mg), Mc was 12.24 mg (9.58-17.51 mg), Mt/Mc was 6.74% (0.66-17.33%). There was a strong correlation between CMR and the histology for Mt, Mc and Mt/ Mc with respectively: r2 = 0.94 (p < 0.001), r2 = 0.91 (p < 0.001), r2 = 0.83 (p < 0.001). Intra- and interobserver reproducibility was 0.97 and 0.8 for Mt; 0.98 and 0.97 for Mc; 0.96 and 0.72 for Mt/Mc, respectively and significantly more trabeculation was observed in the Mc Mutant mice than the controls. CONCLUSION: The proposed semi-automatic quantification software is accurate in comparison to the histology and reproducible in evaluating Mc, Mt and Mt/ Mc on cine CMR.
    Mots-clés : CMR, crmbm, cvs, Genetic mouse model, Left ventricular non-compaction, Semi-automatic segmentation.

  • Gineste, C & Fouré, A 2018, “Heterogeneity of energy metabolism within the tibialis anterior. Is it just an outcome of a specific muscle activation, architecture and composition?”, The Journal of Physiology.

  • Gros, C, De Leener, B, Badji, A, Maranzano, J, Eden, D, Dupont, SM, Talbott, J, Zhuoquiong, R, Liu, Y, Granberg, T, Ouellette, R, Tachibana, Y, Hori, M, Kamiya, K, Chougar, L, Stawiarz, L, Hillert, J, Bannier, E, Kerbrat, A, Edan, G, Labauge, P, Callot, V, Pelletier, J, Audoin, B, Rasoanandrianina, H, Brisset, J-C, Valsasina, P, Rocca, MA, Filippi, M, Bakshi, R, Tauhid, S, Prados, F, Yiannakas, M, Kearney, H, Ciccarelli, O, Smith, S, Treaba, CA, Mainero, C, Lefeuvre, J, Reich, DS, Nair, G, Auclair, V, McLaren, DG, Martin, AR, Fehlings, MG, Vahdat, S, Khatibi, A, Doyon, J, Shepherd, T, Charlson, E, Narayanan, S & Cohen-Adad, J 2018, “Automatic segmentation of the spinal cord and intramedullary multiple sclerosis lesions with convolutional neural networks”, NeuroImage, vol. 184, p. 901-915.
    Résumé : The spinal cord is frequently affected by atrophy and/or lesions in multiple sclerosis (MS) patients. Segmentation of the spinal cord and lesions from MRI data provides measures of damage, which are key criteria for the diagnosis, prognosis, and longitudinal monitoring in MS. Automating this operation eliminates inter-rater variability and increases the efficiency of large-throughput analysis pipelines. Robust and reliable segmentation across multi-site spinal cord data is challenging because of the large variability related to acquisition parameters and image artifacts. In particular, a precise delineation of lesions is hindered by a broad heterogeneity of lesion contrast, size, location, and shape. The goal of this study was to develop a fully-automatic framework - robust to variability in both image parameters and clinical condition - for segmentation of the spinal cord and intramedullary MS lesions from conventional MRI data of MS and non-MS cases. Scans of 1042 subjects (459 healthy controls, 471 MS patients, and 112 with other spinal pathologies) were included in this multi-site study (n = 30). Data spanned three contrasts (T1-, T2-, and T2∗-weighted) for a total of 1943 vol and featured large heterogeneity in terms of resolution, orientation, coverage, and clinical conditions. The proposed cord and lesion automatic segmentation approach is based on a sequence of two Convolutional Neural Networks (CNNs). To deal with the very small proportion of spinal cord and/or lesion voxels compared to the rest of the volume, a first CNN with 2D dilated convolutions detects the spinal cord centerline, followed by a second CNN with 3D convolutions that segments the spinal cord and/or lesions. CNNs were trained independently with the Dice loss. When compared against manual segmentation, our CNN-based approach showed a median Dice of 95% vs. 88% for PropSeg (p ≤ 0.05), a state-of-the-art spinal cord segmentation method. Regarding lesion segmentation on MS data, our framework provided a Dice of 60%, a relative volume difference of -15%, and a lesion-wise detection sensitivity and precision of 83% and 77%, respectively. In this study, we introduce a robust method to segment the spinal cord and intramedullary MS lesions on a variety of MRI contrasts. The proposed framework is open-source and readily available in the Spinal Cord Toolbox.
    Mots-clés : Convolutional neural networks, crmbm, MRI, Multiple sclerosis, Segmentation, snc, Spinal cord.

  • Gros, C, De Leener, B, Dupont, SM, Martin, AR, Fehlings, MG, Bakshi, R, Tummala, S, Auclair, V, McLaren, DG, Callot, V, Cohen-Adad, J & Sdika, M 2018, “Automatic spinal cord localization, robust to MRI contrasts using global curve optimization”, Medical Image Analysis, vol. 44, p. 215-227.
    Résumé : During the last two decades, MRI has been increasingly used for providing valuable quantitative information about spinal cord morphometry, such as quantification of the spinal cord atrophy in various diseases. However, despite the significant improvement of MR sequences adapted to the spinal cord, automatic image processing tools for spinal cord MRI data are not yet as developed as for the brain. There is nonetheless great interest in fully automatic and fast processing methods to be able to propose quantitative analysis pipelines on large datasets without user bias. The first step of most of these analysis pipelines is to detect the spinal cord, which is challenging to achieve automatically across the broad range of MRI contrasts, field of view, resolutions and pathologies. In this paper, a fully automated, robust and fast method for detecting the spinal cord centerline on MRI volumes is introduced. The algorithm uses a global optimization scheme that attempts to strike a balance between a probabilistic localization map of the spinal cord center point and the overall spatial consistency of the spinal cord centerline (i.e. the rostro-caudal continuity of the spinal cord). Additionally, a new post-processing feature, which aims to automatically split brain and spine regions is introduced, to be able to detect a consistent spinal cord centerline, independently from the field of view. We present data on the validation of the proposed algorithm, known as "OptiC", from a large dataset involving 20 centers, 4 contrasts (T2-weighted n = 287, T1-weighted n = 120, T2∗-weighted n = 307, diffusion-weighted n = 90), 501 subjects including 173 patients with a variety of neurologic diseases. Validation involved the gold-standard centerline coverage, the mean square error between the true and predicted centerlines and the ability to accurately separate brain and spine regions. Overall, OptiC was able to cover 98.77% of the gold-standard centerline, with a mean square error of 1.02 mm. OptiC achieved superior results compared to a state-of-the-art spinal cord localization technique based on the Hough transform, especially on pathological cases with an averaged mean square error of 1.08 mm vs. 13.16 mm (Wilcoxon signed-rank test p-value < .01). Images containing brain regions were identified with a 99% precision, on which brain and spine regions were separated with a distance error of 9.37 mm compared to ground-truth. Validation results on a challenging dataset suggest that OptiC could reliably be used for subsequent quantitative analyses tasks, opening the door to more robust analysis on pathological cases.
    Mots-clés : crmbm, Detection, Global optimization, Machine learning, MRI, Segmentation, Spinal cord.

  • Hart, CR, Layec, G, Trinity, JD, Le Fur, Y, Gifford, JR, Clifton, HL & Richardson, RS 2018, “Oxygen availability and skeletal muscle oxidative capacity in patients with peripheral arterial disease: Implications from in vivo and in vitro assessments”, American Journal of Physiology. Heart and Circulatory Physiology.
    Résumé : Evidence suggests that peak skeletal muscle mitochondrial ATP synthesis rate (Vmax) in patients with peripheral arterial disease (PAD) may be attenuated due to disease-related impairments in oxygen (O2) supply. However, in vitro assessments suggest intrinsic deficits in mitochondrial respiration despite ample O2 availability. To address this conundrum, Doppler ultrasound, near infrared spectroscopy (NIRS), phosphorus magnetic resonance spectroscopy (31P-MRS), and high-resolution respirometry were combined to assess convective O2 delivery, tissue oxygenation, Vmax, and skeletal muscle mitochondrial capacity (Complex I+II, State 3 respiration), respectively, in the gastrocnemius muscle of 10 patients with early-stage PAD and 11 physical activity-matched healthy controls (HC). All subjects were studied in free-flow control conditions (FF) and with reactive hyperemia (RH), induced by a period of brief ischemia during the last 30s of submaximal plantar flexion exercise. The patients with PAD repeated the FF and RH trials under hyperoxic conditions (FF+100%O2 and RH+100%O2). Compared to the HC, the patients with PAD exhibited attenuated O2 delivery at the same absolute work rate, and attenuated tissue re-oxygenation and Vmax after relative intensity-matched exercise. Compared to the FF condition, only RH+100%O2 significantly increased convective O2 delivery (~44%), tissue re-oxygenation (~54%), and Vmax (~60%) in PAD (p<0.05) such that Vmax was now not different from the HC. Furthermore, there was no evidence of an intrinsic mitochondrial deficit in PAD, assessed in vitro with adequate O2. Thus, in combination, this comprehensive in vivo and in vitro investigation implicates O2 supply as the predominant factor limiting mitochondrial oxidative capacity in early-stage PAD.
    Mots-clés : Blood Flow, Exercise, Metabolism, Mitochondria, msk, Peripheral Vascular Disease.

  • Kerhervé, HA, Chatel, B, Reboah, S, Rossi, J, Samozino, P & Messonnier, LA 2018, “Comparison of Prolonged Rowing on Fixed and Free-floating Ergometers in Competitive Rowers”, International Journal of Sports Medicine.
    Résumé : This study aimed to compare the effect of a 40-min submaximal rowing exercise performed on ergometers with fixed and free-floating designs. Heart rate, blood lactate concentration, force and rate of force development (RFD) at the handle, stroke rate, duty factor, movement kinematics of upper and lower limbs, and muscle activity of lumbar spine muscles iliocostalis and erector spinae (IC and ESL) were measured at the beginning and at the end of a 40-min rowing exercise at ~60% of peak power output, in eleven competitive rowers. Force of lumbar extension decreased, and blood lactate increased following submaximal exercise on both ergometers. No changes in RFD, duty factor, and muscle activity of IC occurred in response to submaximal exercise. Rowing on DYN elicited higher heart rate and modified rowing kinematics (stroke rate, acceleration of the lower limbs) without changes in temporal or force application patterns compared to rowing on STAT at the same power output. Rowing on DYN was also associated with increased activity of the lumbar spine muscle ESL, which could originate from a greater range of motion, or from an increased lumbar spine muscle activity, at the same overall power.
    Mots-clés : msk.

  • Koubiyr, I, Deloire, M, Coupé, P, Dulau, C, Besson, P, Moroso, A, Planche, V, Tourdias, T, Brochet, B & Ruet, A 2018, “Differential Gray Matter Vulnerability in the 1 Year Following a Clinically Isolated Syndrome”, Frontiers in Neurology, vol. 9, p. 824.
    Résumé : Background and purpose: Whether some gray matter (GM) regions are differentially vulnerable at the early stages of MS is still unknown. The objective of this study is to investigate whether deep and cortical GM are differentially vulnerable after a clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS). Methods: Fifty-six patients with CIS (PwCIS) and 38 healthy controls (HC) had conventional and diffusion tensor imaging (DTI) at baseline and 46 PwCIS and 20 HC were rescanned after 1 year. Deep GM (DGM) volumes, cortical thickness (CTh), and DTI metrics (FA: fractional anisotropy; MD: mean diffusivity) within these structures were calculated for each participant at each time-point and compared between PwCIS and HC. Linear regression models were used to investigate whether baseline DTI parameters could predict GM volume loss over time. Results: At baseline, GM volumes did not differ between PwCIS and HC, but hippocampal MD was higher in PwCIS than HC (p < 0.01). Over 1 year, GM alterations became more widespread with putamen and hippocampus volumes decreasing in PwCIS (p < 0.01), and cortical thinning in different parts of the cortex along with a significant increase of MD. Hippocampus MD at baseline could predict its volume loss (R2 = 0.159; p < 0.05) and cortical thinning was associated to microstructural damage (Spearman's rho ranging from -0.424 to -0.603 with p < 0.003). Conclusion: Along with MS being a diffuse inflammatory disease, GM showed a differential vulnerability at the early stage spreading from hippocampus to the cortex. Hippocampus volume loss could be predicted by its MD at baseline.
    Mots-clés : atrophy, clinically isolated syndrome, diffusion tensor imaging, gray matter, longitudinal, MRI, multiple sclerosis, snc.

  • Lagarde, S, Roehri, N, Lambert, I, Trebuchon, A, McGonigal, A, Carron, R, Scavarda, D, Milh, M, Pizzo, F, Colombet, B, Giusiano, B, Medina Villalon, S, Guye, M, Bénar, C-G & Bartolomei, F 2018, “Interictal stereotactic-EEG functional connectivity in refractory focal epilepsies”, Brain: A Journal of Neurology.
    Résumé : Drug-refractory focal epilepsies are network diseases associated with functional connectivity alterations both during ictal and interictal periods. A large majority of studies on the interictal/resting state have focused on functional MRI-based functional connectivity. Few studies have used electrophysiology, despite its high temporal capacities. In particular, stereotactic-EEG is highly suitable to study functional connectivity because it permits direct intracranial electrophysiological recordings with relative large-scale sampling. Most previous studies in stereotactic-EEG have been directed towards temporal lobe epilepsy, which does not represent the whole spectrum of drug-refractory epilepsies. The present study aims at filling this gap, investigating interictal functional connectivity alterations behind cortical epileptic organization and its association with post-surgical prognosis. To this purpose, we studied a large cohort of 59 patients with malformation of cortical development explored by stereotactic-EEG with a wide spatial sampling (76 distinct brain areas were recorded, median of 13.2 per patient). We computed functional connectivity using non-linear correlation. We focused on three zones defined by stereotactic-EEG ictal activity: the epileptogenic zone, the propagation zone and the non-involved zone. First, we compared within-zone and between-zones functional connectivity. Second, we analysed the directionality of functional connectivity between these zones. Third, we measured the associations between functional connectivity measures and clinical variables, especially post-surgical prognosis. Our study confirms that functional connectivity differs according to the zone under investigation. We found: (i) a gradual decrease of the within-zone functional connectivity with higher values for epileptogenic zone and propagation zone, and lower for non-involved zones; (ii) preferential coupling between structures of the epileptogenic zone; (iii) preferential coupling between epileptogenic zone and propagation zone; and (iv) poorer post-surgical outcome in patients with higher functional connectivity of non-involved zone (within- non-involved zone, between non-involved zone and propagation zone functional connectivity). Our work suggests that, even during the interictal state, functional connectivity is reinforced within epileptic cortices (epileptogenic zone and propagation zone) with a gradual organization. Moreover, larger functional connectivity alterations, suggesting more diffuse disease, are associated with poorer post-surgical prognosis. This is consistent with computational studies suggesting that connectivity is crucial in order to model the spatiotemporal dynamics of seizures.
    Mots-clés : snc.

  • Lefèvre, J, Pepe, A, Muscato, J, De Guio, F, Girard, N, Auzias, G & Germanaud, D 2018, “SPANOL (SPectral ANalysis of Lobes): A Spectral Clustering Framework for Individual and Group Parcellation of Cortical Surfaces in Lobes”, Frontiers in Neuroscience, vol. 12, p. 354.
    Résumé : Understanding the link between structure, function and development in the brain is a key topic in neuroimaging that benefits from the tremendous progress of multi-modal MRI and its computational analysis. It implies, inter alia, to be able to parcellate the brain volume or cortical surface into biologically relevant regions. These parcellations may be inferred from existing atlases (e.g., Desikan) or sets of rules, as would do a neuroanatomist for lobes, but also directly driven from the data (e.g., functional or structural connectivity) with minimum a priori. In the present work, we aimed at using the intrinsic geometric information contained in the eigenfunctions of Laplace-Beltrami Operator to obtain parcellations of the cortical surface based only on its description by triangular meshes. We proposed a framework adapted from spectral clustering, which is general in scope and suitable for the co-parcellation of a group of subjects. We applied it to a dataset of 62 adults, optimized it and revealed a striking agreement between parcels produced by this unsupervised clustering and Freesurfer lobes (Desikan atlas), which cannot be explained by chance. Constituting the first reported attempt of spectral-based fully unsupervised segmentation of neuroanatomical regions such as lobes, spectral analysis of lobes (Spanol) could conveniently be fitted into a multimodal pipeline to ease, optimize or speed-up lobar or sub-lobar segmentation. In addition, we showed promising results of Spanol on smoother brains and notably on a dataset of 15 fetuses, with an interest for both the understanding of cortical ontogeny and the applicative field of perinatal computational neuroanatomy.
    Mots-clés : cortical parcellation, fetal MRI, group-wise analysis, Laplace-Beltrami operator, snc, spectral clustering.

  • Leroi, L, Coste, A, de Rochefort, L, Santin, MD, Valabregue, R, Mauconduit, F, Giacomini, E, Luong, M, Chazel, E, Valette, J, Le Bihan, D, Poupon, C, Boumezbeur, F, Rabrait-Lerman, C & Vignaud, A 2018, “Simultaneous multi-parametric mapping of total sodium concentration, T1, T2 and ADC at 7 T using a multi-contrast unbalanced SSFP”, Magnetic Resonance Imaging.
    Résumé : PURPOSE: Quantifying multiple NMR properties of sodium could be of benefit to assess changes in cellular viability in biological tissues. A proof of concept of Quantitative Imaging using Configuration States (QuICS) based on a SSFP sequence with multiple contrasts was implemented to extract simultaneously 3D maps of applied flip angle (FA), total sodium concentration, T1, T2, and Apparent Diffusion Coefficient (ADC). METHODS: A 3D Cartesian Gradient Recalled Echo (GRE) sequence was used to acquire 11 non-balanced SSFP contrasts at a 6 × 6 × 6 mm3 isotropic resolution with carefully-chosen gradient spoiling area, RF amplitude and phase cycling, with TR/TE = 20/3.2 ms and 25 averages, leading to a total acquisition time of 1 h 18 min. A least-squares fit between the measured and the analytical complex signals was performed to extract quantitative maps from a mono-exponential model. Multiple sodium phantoms with different compositions were studied to validate the ability of the method to measure sodium NMR properties in various conditions. RESULTS: Flip angle maps were retrieved. Relaxation times, ADC and sodium concentrations were estimated with controlled precision below 15%, and were in accordance with measurements from established methods and literature. CONCLUSION: The results illustrate the ability to retrieve sodium NMR properties maps, which is a first step toward the estimation of FA, T1, T2, concentration and ADC of 23Na for clinical research. With further optimization of the acquired QuICS contrasts, scan time could be reduced to be suitable with in vivo applications.
    Mots-clés : Diffusion, Non proton MRI, Sodium, T(1) mapping, T(2) mapping.

  • Lutz, NW & Bernard, M 2018, “Multiparametric quantification of heterogeneity of metal ion concentrations, as demonstrated for [Mg2+] by way of 31P MRS”, Journal of Magnetic Resonance (San Diego, Calif.: 1997), vol. 294, p. 71-82.
    Résumé : Magnesium(II) is the second most abundant intracellular cation in mammals. Non-invasive 31P MRS is currently used to measure intracellular free Mg2+ levels in studies of magnesium deficiency disorders. However, this technique only provides one [Mg2+] value for a given tissue volume (or voxel), based on the chemical shift of the ATP-β (or NTP-β) resonance. We present here an approach for quantifying tissue heterogeneity in regard to [Mg2+], by way of multiple 31P MRS-derived descriptors characterizing the statistical intra-volume distribution of free [Mg2+] values. Our novel paradigm exploits the fact that the lineshape of the ATP-β 31P MRS resonance reflects the statistical distribution of [Mg2+] values within the observed volume (or voxel). Appropriate lineshape analysis reveals multiple quantitative statistical parameters (descriptors) characterizing the [Mg2+] distribution. First, the ATP-β 31P MRS resonance is transformed into a [Mg2+] curve that is used to construct a histogram with our specially developed algorithms. From this histogram, at least eight [Mg2+] descriptors are computed: weighted mean concentration and median concentration, standard deviation of concentration, range of concentration, concentration mode(s), concentration kurtosis, concentration skewness, and concentration entropy. Comprehensive evaluation based on in silico and experimental models demonstrates the validity of this new method. This basic feasibility study should open new avenues for future in vivo studies in physiology and medicine.
    Mots-clés : (31)P NMR, crmbm, Free Mg(2+) concentration, Heterogeneity descriptors, Histograms, Lineshape analysis, Statistical distributions.

  • Maarouf, A, Boutière, C, Rico, A, Audoin, B & Pelletier, J 2018, “How much progress has there been in the second-line treatment of multiple sclerosis: A 2017 update”, Revue Neurologique, vol. 174, no. 6, p. 429-440.
    Résumé : In 1993, the US Food and Drug Administration (FDA) approved the first drug specifically for treating multiple sclerosis (MS). More than two decades later, a dozen such treatments are now available. Of these, four are considered second-line treatments for use in escalation strategies and two new drugs are currently undergoing accreditation procedures. Soon, they will provide clinicians with a range of six effective disease-modifying treatments (DMTs) to thwart the inflammatory processes in MS patients with active disease. However, while such a large number of DMTs for MS can help to control early inflammation, any decisions to be made by clinicians have also been made substantially more complex. This complexity is increased by the lack of head-to-head studies comparing these second-line therapies and the benefit-risk profiles for each of these drugs, which are likely to vary among patients. Ultimately, good awareness of the benefits and, more important, the risks of each MS DMT is crucial for the effective management of inflammation in MS.
    Mots-clés : crmbm, Early treatment, Escalation, Induction, Multiple sclerosis, Second-line therapy, snc.

  • Macia, M, Pecchi, E, Desrois, M, Lan, C, Vilmen, C, Portha, B, Bernard, M, Bendahan, D & Giannesini, B 2018, “Exercise training impacts exercise tolerance and bioenergetics in gastrocnemius muscle of non-obese type-2 diabetic Goto-Kakizaki rat in vivo”, Biochimie.
    Résumé : The functional and bioenergetics impact of regular physical activity upon type-2 diabetic skeletal muscle independently of confounding factors of overweight remains undocumented. Here, gastrocnemius muscle energy fluxes, mitochondrial capacity and mechanical performance were assessed noninvasively and longitudinally in non-obese diabetic Goto-Kakizaki rats using magnetic resonance (MR) imaging and dynamic 31-phosphorus MR spectroscopy (31P-MRS) throughout a 6-min fatiguing bout of exercise performed before, in the middle (4-week) and at the end of an 8-week training protocol consisting in 60-min daily run on a treadmill. The training protocol reduced plasmatic insulin level (-61%) whereas blood glucose and non-esterified fatty acids levels remained unaffected, thereby indicating an improvement of insulin sensitivity. It also increased muscle mitochondrial citrate synthase activity (+45%) but this increase did not enhance oxidative ATP synthesis capacity in working muscle in vivo while glycolytic ATP production was increased (+33%). On the other hand, the training protocol impaired maximal force-generating capacity (-9%), total amount of force produced (-12%) and increased ATP cost of contraction (+32%) during the fatiguing exercise. Importantly, these deleterious effects were transiently worsened in the middle of the 8-week period, in association with reduced oxidative capacity and increased basal [Pi]/[PCr] ratio (an in vivo biomarker of muscle damage). These data demonstrate that the beneficial effect of regular training on insulin sensitivity in non-obese diabetic rat occurs separately from any improvement in muscle mitochondrial function and might be linked to an increased capacity for metabolizing glucose through anaerobic process in exercising muscle.
    Mots-clés : crmbm, cvs, Diabetes, Mitochondrial capacity, msk, Nuclear magnetic resonance, Regular physical activity, Skeletal muscle function.

  • Massire, A, Rasoanandrianina, H, Taso, M, Guye, M, Ranjeva, J-P, Feiweier, T & Callot, V 2018, “Feasibility of single-shot multi-level multi-angle diffusion tensor imaging of the human cervical spinal cord at 7T”, Magnetic Resonance in Medicine, vol. 80, no. 3, p. 947-957.
    Résumé : PURPOSE: Diffusion tensor imaging (DTI), which is frequently used to characterize microstructure impairments in many spinal cord diseases at clinical fields, may benefit from 7T investigations. Yet, it presents specific technical challenges, such as increased magnetic susceptibility-induced image distortions. METHODS: Eight healthy volunteers were scanned at 7T using a prototype diffusion multi-slice multi-angle (MSMA) single-shot spin-echo echo planar imaging (EPI) sequence developed to explore the whole cervical spinal cord while limiting the partial volume effects related to the cord curvature. To mitigate the increased susceptibility-induced distortions encountered at 7T, a reverse phase-encoding strategy was also used. Images acquired from C1-to-C7 were registered to the AMU40 template to automatically extract DTI metrics in gray matter/white matter regions of interest. Effects of B1+ inhomogeneities on the DTI metrics and repeatability of the measurements were also investigated. Lastly, a DTI acquisition with a 400-µm in-plane resolution was acquired on one volunteer to push forward 7T potentialities. RESULTS: The MSMA sequence allowed accessing to high-resolution axial diffusion images sampling the whole cord within a single acquisition. DTI metrics were found in agreement with literature at lower field, stable along a 50-120% relative B1+ variation range, with a mean inter-scan coefficient of variation of 8%. The two--fold spatial-resolution increase of the additional DTI acquisition enabled main white matter tracts visualization on a single-subject basis. CONCLUSION: Although C7-level imaging needs some improvement, this preliminary study shows that transverse 7T DTI of the whole cervical spinal cord is feasible, laying the groundwork for improved multi-parametric MR investigations and microstructure characterization of the spinal cord. Magn Reson Med 80:947-957, 2018. © 2018 International Society for Magnetic Resonance in Medicine.
    Mots-clés : 7T, crmbm, diffusion tensor imaging, multi-slice multi-angle acquisitions, snc, ultra-high-field MRI.

  • Mathieu, C, Desrois, M, Kober, F, Lalevée, N, Lan, C, Fourny, N, Iché-Torres, M, Tran, TT, Lê, LT, Singer, M, Mège, J-L, Bernard, M & Leone, M 2018, “Sex-Mediated Response to the Beta-Blocker Landiolol in Sepsis: An Experimental, Randomized Study”, Critical Care Medicine, vol. 46, no. 7, p. e684-e691.
    Résumé : OBJECTIVES: To investigate any gender effect of the beta-1 adrenergic blocker, landiolol, on cardiac performance and energy metabolism in septic rats, and to explore the expression of genes and proteins involved in this process. DESIGN: Randomized animal study. SETTING: University research laboratory. SUBJECTS: Male and female Wistar rats. INTERVENTIONS: One hour after cecal ligation and puncture, male and female rats were randomly allocated to the following groups: sham male, cecal ligation and puncture male, cecal ligation and puncture + landiolol male, sham female, cecal ligation and puncture female, and cecal ligation and puncture + landiolol female. Cardiac MRI was carried out 18 hours after cecal ligation and puncture to assess in vivo cardiac function. Ex vivo cardiac function measurement and P magnetic resonance spectroscopy were subsequently performed using an isovolumic isolated heart preparation. Finally, we assessed cardiac gene and protein expression. MEASUREMENTS AND MAIN RESULTS: In males, landiolol increased indexed stroke volume by reversing the indexed end-diastolic volume reduction without affecting left ventricle ejection fraction. In females, landiolol did not increase indexed stroke volume and indexed end-diastolic volume but decreased left ventricle ejection fraction. Landiolol had no effect on ex vivo cardiac function and on high-energy phosphate compounds. The effect of landiolol on the gene expression of natriuretic peptide receptor 3 and on protein expression of phosphorylated-AKT:AKT ratio and endothelial nitric oxide synthase was different in males and females. CONCLUSIONS: Landiolol improved the in vivo cardiac performance of septic male rats while deleterious effects were reported in females. Expression of natriuretic peptide receptor 3, phosphorylated-AKT:AKT, and endothelial nitric oxide synthase are signaling pathways to investigate to better understand the sex differences in sepsis.
    Mots-clés : crmbm, cvs.

  • Maurice, F, Dutour, A, Vincentelli, C, Abdesselam, I, Bernard, M, Dufour, H, Le Fur, Y, Graillon, T, Kober, F, Cristofari, P, Jouve, E, Pini, L, Fernandez, R, Chagnaud, C, Brue, T, Castinetti, F & Gaborit, B 2018, “Active cushing syndrome patients have increased ectopic fat deposition and bone marrow fat content compared to cured patients and healthy subjects: a pilot 1H-MRS study”, European Journal of Endocrinology.
    Résumé : OBJECTIVE: Glucocorticoid excess is one of the most important causes of bone disorders. Bone marrow fat (BMF) has been identified as a l new mediator of bone metabolism. Cushing syndrome (CS), is a main regulator of adipose tissue distribution but its impact on BMF is unknown. The objective of the study was to evaluate the effect of chronic hypercortisolism on BMF. DESIGN: This was a cross-sectional study. Seventeen active and seventeen cured ACTH-dependent CS patients along with seventeen controls (matched with the active group for age and sex) were included. METHODS: the BMF content of the femoral neck and L3 vertebrae were measured by 1H-MRS on a 3-Tesla wide-bore magnet. BMD was evaluated in patients using dual-energy X-ray absorptiometry. RESULTS: Active CS patients had higher BMF content both in the femur (82.5±2.6%) and vertebrae (70.1±5.1%) compared to the controls (70.8±3.6%, p=0.013 and 49.0±3.7% p=0.005, respectively). In cured CS patients (average remission time of 43 months), BMF content was not different from controls at both sites (72.3±2.9% (femur) and 46.7%±5.3% (L3)). BMF content was positively correlated with age, fasting plasma glucose, HbA1c, triglycerides and visceral adipose tissue in the whole cohort and negatively correlated with BMD values in the CS patients . CONCLUSIONS: Accumulation of BMF is induced by hypercortisolism. In remission patients BMF reached values of controls. Further studies are needed to determine whether this increase in marrow adiposity in CS is associated with bone loss.
    Mots-clés : crmbm, cvs.

  • Mchinda, S, Varma, G, Prevost, VH, Le Troter, A, Rapacchi, S, Guye, M, Pelletier, J, Ranjeva, J-P, Alsop, DC, Duhamel, G & Girard, OM 2018, “Whole brain inhomogeneous magnetization transfer (ihMT) imaging: Sensitivity enhancement within a steady-state gradient echo sequence”, Magnetic Resonance in Medicine, vol. 79, no. 5, p. 2607-2619.
    Résumé : PURPOSE: To implement, characterize, and optimize an interleaved inhomogeneous magnetization transfer (ihMT) gradient echo sequence allowing for whole-brain imaging within a clinically compatible scan time. THEORY AND METHODS: A general framework for ihMT modelling was developed based on the Provotorov theory of radiofrequency saturation, which accounts for the dipolar order underpinning the ihMT effect. Experimental studies and numerical simulations were performed to characterize and optimize the ihMT-gradient echo dependency with sequence timings, saturation power, and offset frequency. The protocol was optimized in terms of maximum signal intensity and the reproducibility assessed for a nominal resolution of 1.5 mm isotropic. All experiments were performed on healthy volunteers at 1.5T. RESULTS: An important mechanism driving signal optimization and leading to strong ihMT signal enhancement that relies on the dynamics of radiofrequency energy deposition has been identified. By taking advantage of the delay allowed for readout between ihMT pulse bursts, it was possible to boost the ihMT signal by almost 2-fold compared to previous implementation. Reproducibility of the optimal protocol was very good, with an intra-individual error < 2%. CONCLUSION: The proposed sensitivity-boosted and time-efficient steady-state ihMT-gradient echo sequence, implemented and optimized at 1.5T, allowed robust high-resolution 3D ihMT imaging of the whole brain within a clinically compatible scan time. Magn Reson Med 79:2607-2619, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
    Mots-clés : crmbm, dipolar order, dual frequency RF saturation, ihMT, inhomogeneous magnetization transfer, magnetization transfer model, myelin, Provotorov theory of radiofrequency saturation, snc.

  • Merlet, AN, Chatel, B, Hourdé, C, Ravelojaona, M, Bendahan, D, Féasson, L & Messonnier, LA 2018, “How Sickle Cell Disease Impairs Skeletal Muscle Function: Implications in Daily Life”, Medicine and Science in Sports and Exercise.
    Résumé : Sickle cell disease (SCD) is the most frequent life-threatening genetic hemoglobinopathy in the world and occurs due to the synthesis of abnormal hemoglobin S (HbS). HbS-containing red blood cells (RBCs) are fragile, leading to hemolysis and anemia, and adhere to the endothelium, leading to hemorheological and hemodynamical disturbances. In its deoxygenated form, HbS may polymerize, leading to sickling of RBCs and potentially to vaso-occlusive crises. Recent findings observed that sickle cell disease patients demonstrate significant skeletal muscle remodeling and display reduced muscle functional capacities, contributing to exercise intolerance and poor quality of life. While acute high-intensity exercise is not recommended for sickle cell disease patients as it may increase the risk of sickling, regular moderate-intensity physical activity could have beneficial effects on skeletal muscle and more generally on the well-being of sickle cell disease patients. This paper reviews the literature regarding the impact of the disease on muscular tissue characteristics and function, as well as the corresponding implications for SCD patients' quality of life.
    Mots-clés : msk.

  • Messineo, AM, Gineste, C, Sztal, TE, McNamara, EL, Vilmen, C, Ogier, AC, Hahne, D, Bendahan, D, Laing, NG, Bryson-Richardson, RJ, Gondin, J & Nowak, KJ 2018, “L-tyrosine supplementation does not ameliorate skeletal muscle dysfunction in zebrafish and mouse models of dominant skeletal muscle α-actin nemaline myopathy”, Scientific Reports, vol. 8, no. 1, p. 11490.
    Résumé : L-tyrosine supplementation may provide benefit to nemaline myopathy (NM) patients, however previous studies are inconclusive, with no elevation of L-tyrosine levels in blood or tissue reported. We evaluated the ability of L-tyrosine treatments to improve skeletal muscle function in all three published animal models of NM caused by dominant skeletal muscle α-actin (ACTA1) mutations. Highest safe L-tyrosine concentrations were determined for dosing water and feed of wildtype zebrafish and mice respectively. NM TgACTA1D286G-eGFP zebrafish treated with 10 μM L-tyrosine from 24 hours to 6 days post fertilization displayed no improvement in swimming distance. NM TgACTA1D286G mice consuming 2% L-tyrosine supplemented feed from preconception had significant elevations in free L-tyrosine levels in sera (57%) and quadriceps muscle (45%) when examined at 6-7 weeks old. However indicators of skeletal muscle integrity (voluntary exercise, bodyweight, rotarod performance) were not improved. Additionally no benefit on the mechanical properties, energy metabolism, or atrophy of skeletal muscles of 6-7 month old TgACTA1D286G and KIActa1H40Y mice eventuated from consuming a 2% L-tyrosine supplemented diet for 4 weeks. Therefore this study yields important information on aspects of the clinical utility of L-tyrosine for ACTA1 NM.
    Mots-clés : crmbm, msk.

  • Nadjar, Y, Hütter-Moncada, AL, Latour, P, Ayrignac, X, Kaphan, E, Tranchant, C, Cintas, P, Degardin, A, Goizet, C, Laurencin, C, Martzolff, L, Tilikete, C, Anheim, M, Audoin, B, Deramecourt, V, De Gaillarbois, TD, Roze, E, Lamari, F, Vanier, MT & Héron, B 2018, “Adult Niemann-Pick disease type C in France: clinical phenotypes and long-term miglustat treatment effect”, Orphanet Journal of Rare Diseases, vol. 13, no. 1, p. 175.
    Résumé : BACKGROUND: Niemann-Pick disease type C (NP-C) is a neurodegenerative lysosomal lipid storage disease caused by autosomal recessive mutations in the NPC1 or NPC2 genes. The clinical presentation and evolution of NP-C and the effect of miglustat treatment are described in the largest cohort of patients with adolescent/adult-onset NP-C studied to date. METHODS: Observational study based on clinical chart data from adult patients with NP-C (> 18 year old) diagnosed in France between 1990 and 2015. Retrospective data from patients at diagnosis, onset of miglustat therapy (if applicable), and last follow up were analysed. RESULTS: In France, patients with an adolescent-adult neurological form constituted approximately 25% of all NP-C cases diagnosed during the study period. Forty-seven patients (46 with NP-C1 and one with NP-C2; 53% female) were included. Mean ± SD (range) ages at neurological onset and diagnosis were 23.9 ± 12.5 (8-56) years and 34 ± 13.5 (15-65) years, respectively. At presentation, patients mainly had 1) impaired gait due to cerebellar ataxia and/or dystonia, 2) and/or cognitive/behavioural manifestations, 3) and/or psychotic signs. Initially, almost half of patients had only one of the above three neuro-psychiatric manifestations. Vertical supranuclear gaze palsy, usually occurring without patient complaint, was only detected on careful clinical examination and was recorded in most patients (93%) at the time of diagnosis, several years after neurological onset. Thirty-seven patients (79%) received miglustat, among whom seventeen (46%) continued beyond 2 years (at last follow up) to a maximum of 9.8 years. Eight patients (22%) discontinued treatment early due to side effects (n = 3) or perceived lack of efficacy (n = 5).Miglustat treatment duration correlated significantly with reduced neurological worsening (p < 0.001). Treatment for≥2 years was associated with improved patient survival (p = 0.029). Good responses to miglustat were associated with less severe neurological disability at the start of miglustat treatment (p = 0.02). CONCLUSION: The proportion of adolescent/adult-onset NP-C cases diagnosed in France increased 2.5-fold since 2009 compared with the 2000-2008 period due to improved awareness. Adolescent/adult-onset NP-C frequently presented initially with a non-specific isolated neuro-psychiatric manifestation (motor, cognitive or psychotic). Patients with less severe neurological disability responded better to miglustat therapy.
    Mots-clés : Adult-onset, Efficacy, Epidemiology, France, Miglustat, Niemann-pick disease type C, Safety, snc.

  • Petracca, M, Zaaraoui, W, Cocozza, S, Vancea, R, Howard, J, Heinig, MM, Fleysher, L, Oesingmann, N, Ranjeva, J-P & Inglese, M 2018, “An MRI evaluation of grey matter damage in African Americans with MS”, Multiple Sclerosis and Related Disorders, vol. 25, p. 29-36.
    Résumé : OBJECTIVE: Multiple sclerosis (MS) is less prevalent in African Americans (AAs) than Caucasians (CAs) but in the former the disease course tends to be more severe. In order to clarify the MRI correlates of disease severity in AAs, we performed a multimodal brain MRI study to comprehensively assess the extent of grey matter (GM) damage and the degree of functional adaptation to structural damage in AAs with MS. METHODS: In this cross-sectional study, we characterized GM damage in terms of focal lesions and volume loss and functional adaptation during the execution of a simple motor task on a sample of 20 AAs and 20 CAs with MS and 20 healthy controls (CTRLs). RESULTS: In AAs, we observed a wider range of EDSS scores than CAs, with multisystem involvement being more likely in AAs (p < 0.01). While no significant differences were detected in lesion loads and global brain volumes, AAs showed regional atrophy in the posterior lobules of cerebellum, temporo-occipital and frontal regions in comparison with CAs (p < 0.01), with cerebellar atrophy being the best metric in differentiating AAs from CAs (p = 0.007, AUC = 0.96 and p = 0.005, AUC = 0.96, respectively for right and left cerebellar clusters). In AAs, the functional analysis of cortical activations showed an increase in task-related activation of areas involved in high level processing and a decreased activation in the medial prefrontal cortex compared to CAs. INTERPRETATION: In our study, the direct comparison of AAs and CAs points to cerebellar atrophy as the main difference between subgroups.
    Mots-clés : African Americans, crmbm, Grey matter, Multiple Sclerosis, snc.

  • Proix, T, Jirsa, VK, Bartolomei, F, Guye, M & Truccolo, W 2018, “Predicting the spatiotemporal diversity of seizure propagation and termination in human focal epilepsy”, Nature Communications, vol. 9, no. 1, p. 1088.
    Résumé : Recent studies have shown that seizures can spread and terminate across brain areas via a rich diversity of spatiotemporal patterns. In particular, while the location of the seizure onset area is usually invariant across seizures in an individual patient, the source of traveling (2-3 Hz) spike-and-wave discharges during seizures can either move with the slower propagating ictal wavefront or remain stationary at the seizure onset area. Furthermore, although many focal seizures terminate synchronously across brain areas, some evolve into distinct ictal clusters and terminate asynchronously. Here, we introduce a unifying perspective based on a new neural field model of epileptic seizure dynamics. Two main mechanisms, the co-existence of wave propagation in excitable media and coupled-oscillator dynamics, together with the interaction of multiple time scales, account for the reported diversity. We confirm our predictions in seizures and tractography data obtained from patients with pharmacologically resistant epilepsy. Our results contribute toward patient-specific seizure modeling.
    Mots-clés : snc.

  • Ridley, B, Nagel, AM, Bydder, M, Maarouf, A, Stellmann, J-P, Gherib, S, Verneuil, J, Viout, P, Guye, M, Ranjeva, J-P & Zaaraoui, W 2018, “Distribution of brain sodium long and short relaxation times and concentrations: a multi-echo ultra-high field23Na MRI study”, Scientific Reports, vol. 8, no. 1, p. 4357.
    Résumé : Sodium (23Na) MRI proffers the possibility of novel information for neurological research but also particular challenges. Uncertainty can arise in in vivo23Na estimates from signal losses given the rapidity of T2* decay due to biexponential relaxation with both short (T2*short) and long (T2*long) components. We build on previous work by characterising the decay curve directly via multi-echo imaging at 7 T in 13 controls with the requisite number, distribution and range to assess the distribution of both in vivo T2*shortand T2*longand in variation between grey and white matter, and subregions. By modelling the relationship between signal and reference concentration and applying it to in vivo23Na-MRI signal,23Na concentrations and apparent transverse relaxation times of different brain regions were measured for the first time. Relaxation components and concentrations differed substantially between regions of differing tissue composition, suggesting sensitivity of multi-echo23Na-MRI toward features of tissue composition. As such, these results raise the prospect of multi-echo23Na-MRI as an adjunct source of information on biochemical mechanisms in both physiological and pathophysiological states.
    Mots-clés : crmbm, snc.

  • Salaun, E, Clavel, M-A, Rodés-Cabau, J & Pibarot, P 2018, “Bioprosthetic aortic valve durability in the era of transcatheter aortic valve implantation”, Heart (British Cardiac Society).
    Résumé : The main limitation of bioprosthetic valves is their limited durability, which exposes the patient to the risk of aortic valve reintervention. Transcatheter aortic valve implantation (TAVI) is considered a reasonable alternative to surgical aortic valve replacement (SAVR) in patients with intermediate or high surgical risk. TAVI is now rapidly expanding towards the lower risk populations. Although the results of midterm durability of the transcatheter bioprostheses are encouraging, their long-term durability remains largely unknown. The objective of this review article is to present the definition, mechanisms, incidence, outcome and management of structural valve deterioration of aortic bioprostheses with specific emphasis on TAVI. The structural valve deterioration can be categorised into three stages: stage 1: morphological abnormalities (fibrocalcific remodelling and tear) of bioprosthesis valve leaflets without hemodynamic valve deterioration; stage 2: morphological abnormalities and moderate hemodynamic deterioration (increase in gradient and/or new onset of transvalvular regurgitation); and stage 3: morphological abnormalities and severe hemodynamic deterioration. Several specifics inherent to the TAVI including valve oversizing, manipulation, delivery, positioning and deployment may cause injuries to the valve leaflets and increase leaflet mechanical stress, which may limit the long-term durability of transcatheter bioprostheses. The selection of the type of aortic valve replacement and bioprosthesis should thus take into account the ratio between the demonstrated durability of the bioprostheses versus the life expectancy of the patient. Pending the publication of robust data on long-term durability of transcatheter bioprostheses, it appears reasonable to select SAVR with a bioprosthesis model that has well-established long-term durability in patients with low surgical risk and long life expectancy.
    Mots-clés : aortic regurgitation, aortic stenosis, cardiac computer tomographic (CT) imaging, cvs, echocardiography, prosthetic heart valves.

  • Salaun, E, Mahjoub, H, Dahou, A, Mathieu, P, Larose, É, Després, J-P, Rodés-Cabau, J, Arsenault, BJ, Puri, R, Clavel, M-A & Pibarot, P 2018, “Hemodynamic Deterioration of Surgically Implanted Bioprosthetic Aortic Valves”, Journal of the American College of Cardiology, vol. 72, no. 3, p. 241-251.
    Résumé : BACKGROUND: Dysmetabolic profile has been associated with native aortic valve stenosis. However, there are limited data on the effects of an atherogenic milieu and its potential implications on the structural and hemodynamic deterioration of aortic bioprosthetic valves. OBJECTIVES: This prospective longitudinal study sought to determine the predictors and impact on outcomes of hemodynamic valve deterioration (HVD) of surgically implanted aortic bioprostheses. METHODS: A total of 137 patients with an aortic bioprosthesis implanted for a median time of 6.7 (interquartile range: 5.1 to 9.1) years prospectively underwent a first (baseline) assessment with complete Doppler echocardiography, quantitation of bioprosthesis leaflet calcification by multidetector computed tomography (CT), and a fasting blood sample to assess cardiometabolic risk profile. All patients underwent a second (follow-up) Doppler echocardiography examination at 3 (interquartile range: 2.9 to 3.3) years post-baseline visit. HVD was defined by an annualized change in mean transprosthetic gradient ≥3 mm Hg/year and/or worsening or transprosthetic regurgitation by ≥1/3 class. The primary endpoint was a nonhierarchical composite of death from any cause or aortic reintervention procedure (redo surgical valve replacement or transcatheter valve-in-valve implantation) for bioprosthesis failure. RESULTS: Thirty-four patients (25.6%) had leaflet calcification on baseline CT, and 18 patients (13.1%) developed an HVD between baseline and follow-up echocardiography. Fifty-two patients (38.0%) met the primary endpoint during subsequent follow-up after the second echocardiographic examination. Leaflet calcification (hazard ratio [HR]: 2.58; 95% confidence interval [CI]: 1.35 to 4.82; p = 0.005) and HVD (HR: 5.12; 95% CI: 2.57 to 9.71; p < 0.001) were independent predictors of the primary endpoint. Leaflet calcification, insulin resistance (homeostatic model assessment index ≥2.7), lipoprotein-associated phospholipase A2 activity (Lp-PLA2 per 0.1 nmol/min/ml increase), and high level of proprotein convertase subtilisin/kexin 9 (PCSK9) (≥305 ng/ml) were associated with the development of HVD after adjusting for age, sex, and time interval since aortic valve replacement. CONCLUSIONS: HVD identified by Doppler echocardiography is independently associated with a marked increase in the risk of valve reintervention or mortality in patients with a surgical aortic bioprosthesis. A dysmetabolic profile characterized by elevated plasma Lp-PLA2, PCSK9, and homeostatic model assessment index was associated with increased risk of HVD. The presence of leaflet calcification as detected by CT was a strong predictor of HVD, providing incremental risk-predictive capacity.
    Mots-clés : bioprosthesis, calcification, computed tomography, cvs, dysmetabolic, structural valve degeneration.

  • Salaun, E, Sportouch, L, Barral, P-A, Hubert, S, Lavoute, C, Casalta, A-C, Pradier, J, Ouk, D, Casalta, J-P, Lambert, M, Gouriet, F, Gaubert, J-Y, Dehaene, A, Jacquier, A, Tessonnier, L, Haentjens, J, Theron, A, Riberi, A, Cammilleri, S, Grisoli, D, Jaussaud, N, Collart, F, Bonnet, J-L, Camoin, L, Renard, S, Cuisset, T, Avierinos, J-F, Lepidi, H, Mundler, O, Raoult, D & Habib, G 2018, “Diagnosis of Infective Endocarditis After TAVR: Value of a Multimodality Imaging Approach”, JACC. Cardiovascular imaging, vol. 11, no. 1, p. 143-146.
    Mots-clés : infective endocarditis, multi-imaging, PET/CT, TAVI, TAVR.

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