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International audience; Purpose: This study aimed at determining through MRI investigations, force and soreness assessments whether the modulation of muscle length is a relevant strategy for minimising neuromuscular electrical stimulation (NMES)-induced muscle damage in young healthy participants.Methods: Comparison of 2 NMES sessions (40 isometric electrically-evoked contractions of the knee extensors) was randomly performed on 1 knee flexed at 50° (short muscle length) and the contralateral at 100° (long muscle length) in a single group of healthy participants. Indirect markers of muscle damage including changes in maximal voluntary isometric contraction (MVC) force, muscle volume and transverse relaxation time (T2) were measured before, 2 days (D2), 4 days (D4) and 7 days (D7) after the NMES sessions in each limb of the ten participants.Results: Although stimulation intensity was similar during the NMES session on both limbs, significantly lower force production was recorded at long muscle length (peak at 30 ± 5% MVC force) as compared to short muscle length (peak at 61 ± 12% MVC force). In the following days, MVC force at long muscle length was decreased from D2 to D7, whereas no significant change occurred at short muscle length. Increases in muscle volume and T2 were found at each time point in stimulated muscles at long muscle length, whereas no change was found at short muscle length.Conclusion: For the same stimulation intensity, NMES-induced isometric contractions generate higher knee extension force output and result in lower muscle tissues alterations that could be related to a lower intramuscular shear strain when exercise is performed at short muscle length.

Background: Radiologically isolated syndrome (RIS) is characterized by patients with asymptomatic T2 hypersignals detected by brain MRI fulfilling dissemination in space criteria and is suggestive of subclinical multiple sclerosis (MS). In previous studies, it was demonstrated that visual evoked potential and cerebrospinal fluid help to identify pejorative markers in converting to MS. Objective: To date the cognitive function has never been investigated in a cohort of RIS. The objective of this study was to investigate cognitive function in a cohort of 26 RIS patients. Methods: We prospectively assessed the BCcogSEP (a French adaptation of the Brief Repeatable Battery (BRB) including eight cognitive tests) of 26 patients with RIS, compared with 26 MS patients and 26 healthy subjects matched for age, sex and level of education. Results: When comparing the three groups, the cognitive performance was significantly lower in the RIS and MS groups compared with healthy subjects for the Paced Auditory Serial Addition Test (PASAT) 3 seconds ( p = 0.002), phonemic fluencies ( p = 0.02), the code of the WAIS ( p = 0.05), the direct ( p = 0.002) or indirect ( p = 0.007) digit span test, the cross-taping test ( p = 0.019) and Go—No-Go ( p = 0.001). When we compared RIS and MS, the cognitive performance was significantly lower in MS patients for the direct span number ( p = 0.003) and cross-tapping test ( p = 0.05). We did not find significant differences between the three groups for the other tests. We did not find a correlation between clinical, biological and MRI results and cognitive dysfunctions. Conclusions: This study confirms the recently developed concept of RIS patients who present similar features to MS patients. Further studies are necessary to confirm these initial results and to correlate cognitive disorders with MRI surrogate markers.

Although citrulline malate (CM; CAS 54940-97-5, Stimol) is used against fatigue states, its anti-asthenic effect remains poorly documented. The objective of this double-blind study was to evaluate the effect of oral ingestion of CM on a rat model of asthenia, using in situ (31)Phosphorus magnetic resonance spectroscopy ((31)P-MRS). Muscle weakness was induced by intraperitoneal injections of Klebsiella pneumoniae endotoxin (lipopolysaccharides at 3 mg/kg) at t(0) and t(0)+24 h. For each animal, muscle function was investigated strictly non-invasively before (t(0)-24 h) and during (t(0)+48 h) endotoxemia, through a standardized rest-stimulation-recovery protocol. The transcutaneous electrical stimulation protocol consisted of 5.7 min of repeated isometric contractions at a frequency of 3.3 Hz, and force production was measured with an ergometer. CM supplementation in endotoxemic animals prevented the basal phosphocreatine/ATP ratio reduction and normalized the intracellular pH (pH(i)) time-course during muscular activity as a sign of an effect at the muscle energetics level. In addition, CM treatment avoided the endotoxemia-induced decline in developed force. These results demonstrate the efficiency of CM for limiting skeletal muscle dysfunction in rats treated with bacterial endotoxin.

The mechanical and structural properties of skin subjected to expansion have been widely investigated in the context of plastic surgery. To determine the actual metabolic state of skin following skin expander placement, we determined the basic biochemical parameters for various conditions of postsurgical wound healing and cutaneous growth. Studying, for the first time, comprehensive metabolic profiles ("metabolomics") of the skin in a minipig model, we found that the lactate/alanine ratios were significantly increased (p

Purpose To investigate the capacity of multimodal MR to detect endothelial hyperplasia (EH), which has been linked to the aggressiveness of gliomas and which is so far only detected by biopsy, an invasive technique that prevents repeated measurements and early detection. Materials and Methods A total of 26 patients with low-grade gliomas participated in the study. All underwent a histopathological analysis and a multimodal MR examination (spectroscopic, anatomic, diffusion, perfusion, and postcontrast imaging). Results EH was present (EH+) in 15 patients and absent (EH–) in 11. No differences were observed between EH– and EH+ groups when comparing spectroscopic and diffusion parameters. Perfusion measurements, however, allowed us to distinguish EH+ from EH–: the relative regional cerebral blood flow (rCBF) was found equal to 3.23 ± 2.05 for EH+ and 1.33 ± 0.46 for EH– (P = 0.006). Conclusion We have observed a strong correlation between the presence of EH and the increase of rCBF. Compared to conventional imaging, MR perfusion provides additional and complementary information that may be used for biopsy guidance, early detection of tumor aggressiveness, and noninvasive follow-ups. J. Magn. Reson. Imaging 2007;26:52–60. © 2007 Wiley-Liss, Inc.

AIM: To quantify the wrist cartilage cross-sectional area in humans from a 3D magnetic resonance imaging (MRI) dataset and to assess the corresponding reproducibility. METHODS: The study was conducted in 14 healthy volunteers (6 females and 8 males) between 30 and 58 years old and devoid of articular pain. Subjects were asked to lie down in the supine position with the right hand positioned above the pelvic region on top of a home-built rigid platform attached to the scanner bed. The wrist was wrapped with a flexible surface coil. MRI investigations were performed at 3T (Verio-Siemens) using volume interpolated breath hold examination (VIBE) and dual echo steady state (DESS) MRI sequences. Cartilage cross sectional area (CSA) was measured on a slice of interest selected from a 3D dataset of the entire carpus and metacarpal-phalangeal areas on the basis of anatomical criteria using conventional image processing radiology software. Cartilage cross-sectional areas between opposite bones in the carpal region were manually selected and quantified using a thresholding method. RESULTS: Cartilage CSA measurements performed on a selected predefined slice were 292.4 ± 39 mm2 using the VIBE sequence and slightly lower, 270.4 ± 50.6 mm2, with the DESS sequence. The inter (14.1%) and intra (2.4%) subject variability was similar for both MRI methods. The coefficients of variation computed for the repeated measurements were also comparable for the VIBE (2.4%) and the DESS (4.8%) sequences. The carpus length averaged over the group was 37.5 ± 2.8 mm with a 7.45% between-subjects coefficient of variation. Of note, wrist cartilage CSA measured with either the VIBE or the DESS sequences was linearly related to the carpal bone length. The variability between subjects was significantly reduced to 8.4% when the CSA was normalized with respect to the carpal bone length. CONCLUSION: The ratio between wrist cartilage CSA and carpal bone length is a highly reproducible standardized measurement which normalizes the natural diversity between individuals.

We present a method for the analysis of basal ganglia (including the thalamus) for accurate detection of human spongiform encephalopathy in multisequence magnetic resonance imaging (MRI) of the brain. One common feature of most forms of prion protein diseases is the appearance of hyperintensities in the deep grey matter area of the brain in T2-weighted magnetic resonance (MR) images. We employ T1, T2, and Flair-T2 MR sequences for the detection of intensity deviations in the internal nuclei. First, the MR data are registered to a probabilistic atlas and normalized in intensity. Then smoothing is applied with edge enhancement. The segmentation of hyperintensities is performed using a model of the human visual system. For more accurate results, a priori anatomical data from a segmented atlas are employed to refine the registration and remove false positives. The results are robust over the patient data and in accordance with the clinical ground truth. Our method further allows the quantification of intensity distributions in basal ganglia. The caudate nuclei are highlighted as main areas of diagnosis of sporadic Creutzfeldt-Jakob Disease (sCJD), in agreement with the histological data. The algorithm permitted the classification of the intensities of abnormal signals in sCJD patient FLAIR images with a higher hypersignal in caudate nuclei (10/10) and putamen (6/10) than in thalami. Defining normalized MRI measures of the intensity relations between the internal grey nuclei of patients, we robustly differentiate sCJD and variant CJD (vCJD) patients, in an attempt to create an automatic classification tool of human spongiform encephalopathies.

Following our previous reports based on parametric MRI methods (T 2 -weighted MRI, statistical mapping analysis of magnetization transfer ratio images and functional MRI) applied to a population of 18 patients with clinically isolated syndrome suggestive of multiple sclerosis, we have reviewed the possible structural and functional surrogates of MS that could explain the subtle cognitive impairment related to attention and working memory deficits evaluated with paced auditory serial addition test (PASAT). We propose that the brain substrates underlying cognitive impairment observed at the very early stage of MS are multifactorial. Several components could influence PASAT performances in patients: i) the extent of diffuse white matter damage, ii) the location of visible and non visible lesions, iii) the connectivity efficiency between distant brain functional areas involved in working memory processes and iv) the cortical reorganization. Nevertheless, individually, each of these parameters may have few influences on PASAT performance in patients. Using a multiregression model built with independent MR parameters, a very good evaluation of PASAT scores has been obtained in this limited number of patients explaining 90% of the variance. In conclusion, the different aspects of tissue and functional pathological brain underpinnings must be accounted to monitor accurately new therapeutic strategies for the treatment of early cognitive deficits related to MS.

Following our previous reports based on parametric MRI methods (T(2)-weighted MRI, statistical mapping analysis of magnetization transfer ratio images and functional MRI) applied to a population of 18 patients with clinically isolated syndrome suggestive of multiple sclerosis, we have reviewed the possible structural and functional surrogates of MS that could explain the subtle cognitive impairment related to attention and working memory deficits evaluated with paced auditory serial addition test (PASAT). We propose that the brain substrates underlying cognitive impairment observed at the very early stage of MS are multifactorial. Several components could influence PASAT performances in patients: i) the extent of diffuse white matter damage, ii) the location of visible and non visible lesions, iii) the connectivity efficiency between distant brain functional areas involved in working memory processes and iv) the cortical reorganization. Nevertheless, individually, each of these parameters may have few influences on PASAT performance in patients. Using a multiregression model built with independent MR parameters, a very good evaluation of PASAT scores has been obtained in this limited number of patients explaining 90% of the variance. In conclusion, the different aspects of tissue and functional pathological brain underpinnings must be accounted to monitor accurately new therapeutic strategies for the treatment of early cognitive deficits related to MS.

International audience

International audience

International audience; Premature births are increasing worldwide (about 15 millions per year) due to several reasons (an advanced maternal age, fertility treatments, stress, smoking, nutritional deficiencies) and lead to a high societal overall cost. Among neonatal care procedures, the clinical nutrition practices are essential to promote the development and to minimize the sequelae. Prema-ture newborns are at major risk of death by infections due to the immaturity of their intestine. Human milk provides not only nutrients but also a plethora of biologically active components that are tailored to contribute to the development of the intes-tinal tract early in postnatal life. Among them, some bioactive molecules exhibit trophic effects (LC-PUFA, sphingomyelin, IGF-I and IGF-II, EGF, insulin, leptin, adiponectin, lactoferrin, lactadherin, probiotics, prebiotics, miRNA) or are part of the intestinal cell membranes (PUFA, LC-PUFA, phospholipids, sphingolipids, cholesterol), others educate the intestine for innate microbial recognition (sCD14, sTLR-2, miRNA), many of them display direct fighting against pathogens (some fatty acids and monoglycerides, some phospholipids and sphingolipids, BSSL, insulin, lactoferrin, sIgAs, MUC-1, lactadherin, probiotics, prebiotics), or contribute to establish the gut microbiota (LC-PUFA, lactoferrin, probiotics, prebiotics). A syn-ergetic action exists between several bioactive molecules. All together these precious agents regulate the maturation of the intestinal mucosal barrier, and might program early in postnatal life the future adult intestinal health. This review lists the main bioactive compounds and addresses their plausible roles and mechanisms of action.

Our goal was to build a probabilistic atlas and anatomical template of the human cervical and thoracic spinal cord (SC) that could be used for segmentation algorithm improvement, parametric group studies, and enrichment of biomechanical modelling. High-resolution axial T2*-weighted images were acquired at 3T on 15 healthy volunteers using a multi-echo–gradient-echo sequence (1 slice per vertebral level from C1 to L2). After manual segmentation, linear and affine co-registrations were performed providing either inter-individual morphometric variability maps, or substructure probabilistic maps [CSF, white and grey matter (WM/GM)] and anatomical SC template. The larger inter-individual morphometric variations were observed at the thoraco-lumbar levels and in the posterior GM. Mean SC diameters were in agreement with the literature and higher than post-mortem measurements. A representative SC MR template was generated and values up to 90 and 100 % were observed on GM and WM-probability maps. This work provides a probabilistic SC atlas and a template that could offer great potentialities for parametrical MRI analysis (DTI/MTR/fMRI) and group studies, similar to what has already been performed using a brain atlas. It also offers great perspective for biomechanical models usually based on post-mortem or generic data. Further work will consider integration into an automated SC segmentation pipeline.

Amnesic mild cognitive impairment (aMCI) is a heterogeneous syndrome that could be subdivided into distinct neuropsychological variants. To investigate relationships between the neuropsychological profile of memory impairment at baseline and the neuroimaging pattern of grey matter (GM) loss over 18 months, we performed a prospective volumetric brain study on 31 aMCI patients and 29 matched controls. All subjects were tested at baseline using a standardized neuropsychological battery, which included the Free and Cued Selective Recall Reminding Test (FCSRT) for the assessment of verbal declarative memory. Over 18 months, patients with impaired free recall but normal total recall (high index of cueing) on the FCSRT developed subcortical and frontal GM loss, while patients with impaired free and total recall (low index of cueing) developed GM atrophy within the left anterior and lateral temporal lobe. In summary, cued recall deficits are associated with a progression of atrophy that closely parallels the spatiotemporal distribution of neurofibrillary degeneration in early Alzheimer's disease (AD), indicating possible AD pathological changes.

Large-scale longitudinal multi-site MRI brain morphometry studies are becoming increasingly crucial to characterize both normal and clinical population groups using fully automated segmentation tools. The test-retest reproducibility of morphometry data acquired across multiple scanning sessions, and for different MR vendors, is an important reliability indicator since it defines the sensitivity of a protocol to detect longitudinal effects in a consortium. There is very limited knowledge about how across-session reliability of morphometry estimates might be affected by different 3T MRI systems. Moreover, there is a need for optimal acquisition and analysis protocols in order to reduce sample sizes. A recent study has shown that the longitudinal FreeSurfer segmentation offers improved within session test-retest reproducibility relative to the cross-sectional segmentation at one 3T site using a nonstandard multi-echo MPRAGE sequence. In this study we implement a multi-site 3T MRI morphometry protocol based on vendor provided T1 structural sequences from different vendors (3D MPRAGE on Siemens and Philips, 3D IR-SPGR on GE) implemented in 8 sites located in 4 European countries. The protocols used mild acceleration factors (1.5-2) when possible. We acquired across-session test-retest structural data of a group of healthy elderly subjects (5 subjects per site) and compared the across-session reproducibility of two full-brain automated segmentation methods based on either longitudinal or cross-sectional FreeSurfer processing. The segmentations include cortical thickness, intracranial, ventricle and subcortical volumes. Reproducibility is evaluated as absolute changes relative to the mean (%), Dice coefficient for volume overlap and intraclass correlation coefficients across two sessions. We found that this acquisition and analysis protocol gives comparable reproducibility results to previous studies that used longer acquisitions without acceleration. We also show that the longitudinal processing is systematically more reliable across sites regardless of MRI system differences. The reproducibility errors of the longitudinal segmentations are on average approximately half of those obtained with the cross sectional analysis for all volume segmentations and for entorhinal cortical thickness. No significant differences in reliability are found between the segmentation methods for the other cortical thickness estimates. The average of two MPRAGE volumes acquired within each test-retest session did not systematically improve the across-session reproducibility of morphometry estimates. Our results extend those from previous studies that showed improved reliability of the longitudinal analysis at single sites and/or with non-standard acquisition methods. The multi-site acquisition and analysis protocol presented here is promising for clinical applications since it allows for smaller sample sizes per MRI site or shorter trials in studies evaluating the role of potential biomarkers to predict disease progression or treatment effects.

Recent studies have suggested that intra-axonal sodium accumulation contribute to axonal degeneration in patients with MS. Advances in MRI hardware and software allow acquisition of brain sodium signal in vivo. This review begins with a summary of the experimental evidence for impairment of sodium homeostasis in MS. Then, MRI methods for sodium acquisition are reviewed and the application of the techniques in patients with MS is discussed. Sodium imaging and ultra-high field MRI have the potential to provide tissue-specific markers of neurodegeneration in MS.

RADIOLOGIE ET IMAGERIE MEDICALE : Musculosquelettique - Neurologique - Maxillofaciale - 31-620-A-10

0035-3787 (Electronic) 0035-3787 (Linking) Journal article; INTRODUCTION: Health-related quality of life (HRQL) measurements have become an important outcome both for population health assessment and for evaluating treatments and care management. HRQL indicators require completion of a well-validated questionnaire. Few specific questionnaires are available for French multiple sclerosis (MS) patients. The Multiple Sclerosis International Quality of Life questionnaire (MusiQoL), a self-administered and multidimensional questionnaire, was co-developed and validated in 17 countries, including France. We report the main results of the French clinical validity of this instrument. METHODS: The French patients were recruited between January 2004 and February 2005. The main inclusion criteria were: diagnosis of MS according to McDonald criteria, age over 18 years, having given informed consent. The self-administered survey materials that were completed by the patients included the MusiQoL, the generic HRQL questionnaire SF36, and one checklist of 14 MS-specific symptoms reported by the patients. MusiQoL comprises 31 items describing nine dimensions: activity of daily living (eight items), psychological well-being (four), symptoms (three), friends relationships (four), family relationships (three), satisfaction with health care (three), sentimental and sexual life (two), coping (two), and rejection (two). A global index score is computed. Patients were evaluated at inclusion (T0), and retested 21+/-7 days later (T1). At T0, an experienced neurologist collected sociodemographic data, clinical history related or unrelated to the MS condition, treatments. At T1, change in the patient's health status from T0 was reported. RESULTS: The analyses were performed with data from 179 subjects. The mean patient age was 44.1 years (SD: 11.5); there were 120 women and 59 men, 58.1% were unemployed, 13.6% had a tertiary educational level. MS clinical forms were 69 relapsing-remitting, 47 secondary-progressive, 37 primary-progressive, and nine clinically isolated syndrome. The EDSS median was 4.5 (25-75(th) percentiles: 2.5-6.0). The final French version showed satisfactory psychometric properties (external validity, internal consistency, reliability, reproducibility, and acceptability). CONCLUSION: The availability of a reliable and valid French version of MusiQoL, a self-administered and multidimensional questionnaire, co-developed in different countries, enables evaluation of QoL in French MS patients that are eligible for international multicenter studies.

International audience; OBJECTIVE: The authors aimed to determine the ability of resting-state functional connectivity MRI (fcMRI) to lateralise/localise the epileptogenic zone in patients presenting with mesial temporal lobe epilepsy (MTLE) at the individual level. METHODS: Basal functional connectivity (BFC) was evaluated in each hemisphere of 22 MTLE patients. 200 volumes were acquired using a single-shot GE-EPI sequence during a resting period of 10 min at 1.5 T. The signal time-course was extracted from 10 regions of interest (ROIs), five ROIs in each hemisphere, usually involved in epileptogenic networks of MTLE. Normalised correlation coefficients between pairs of ROIs signal time-courses were computed to reflect BFC. Based on normative BFC values obtained from 36 controls, the number of BFC decreases and increases were determined in each hemisphere for each patient. RESULTS: BFC decreases were found bilaterally, although the number of decreased links was significantly higher in the epileptogenic side (p=0.025). Conversely, BFC increases were found almost exclusively in the contralateral lobe leading to a strong test effect for locating the non-epileptic lobe with a sensitivity of 64% and a specificity of 91% (p

We quantified energy production in 7 prepubescent boys (11.7 ± 0.6 yr) and 10 men (35.6 ± 7.8 yr) using31P-magnetic resonance spectroscopy to investigate whether development affects muscle energetics, given that resistance to fatigue has been reported to be larger before puberty. Each subject performed a finger flexions exercise at 0.7 Hz against a weight adjusted to 15% of their maximal voluntary strength for 3 min, followed by a 15-min recovery period. The total energy cost was similar in both groups throughout the exercise bout, whereas the interplay of the different metabolic pathways was different. At the onset of exercise, children exhibited a higher oxidative contribution (50 ± 15% in boys and 25 ± 8% in men, P < 0.05) to ATP production, whereas the phosphocreatine breakdown contribution was reduced (40 ± 10% in boys and 53 ± 12% in men, P < 0.05), likely as a compensatory mechanism. The anaerobic glycolysis activity was unaffected by maturation. The recovery phase also disclosed differences regarding the rates of proton efflux (6.2 ± 2.5 vs. 3.8 ± 1.9 mM·pH unit−1·min−1, in boys and men, respectively, P < 0.05), and phosphocreatine recovery, which was significantly faster in boys than in men (rate constant of phosphocreatine recovery: 1.3 ± 0.5 vs. 0.7 ± 0.4 min−1; Vmax: 37.5 ± 14.5 vs. 21.1 ± 12.2 mM/min, in boys and men, respectively, P < 0.05). Our results obtained in vivo clearly showed that maturation affects muscle energetics. Children relied more on oxidative metabolism and less on creatine kinase reaction to meet energy demand during exercise. This phenomenon can be explained by a greater oxidative capacity, probably linked to a higher relative content in slow-twitch fibers before puberty.

International audience; OBJECT: While occurrence of motor cortical reorganization has been clearly demonstrated in patients with multiple sclerosis (MS), it is not yet clear whether this cortical reorganization constitutes a response to cortico-spinal lesions or to more diffuse damage affecting the neuronal network involved in motor act preparation, or both. We proposed to investigate the changes in the activation pattern during a simple motor task devoid of cortico-spinal dysfunction occurring in patients with clinically isolated syndrome (CIS) suggestive of MS. MATERIALS AND METHODS: Among 15 right-handed CIS patients, we selected eight patients with a preserved central motor pathway established by motor evoked potentials. Ten healthy right-handed gender- and age-matched volunteers were also included. After morphological MRI, subjects performed calibrated conjugated finger flexion and extension movements during fMRI acquisition. RESULTS: In CIS patients, simple movements of the non-dominant hand induced recruitment of the anterior cingulate cortex (BA32) usually involved in complex motor movements. This reorganization was correlated with the diffuse brain tissue damage (brain T lesion load). CONCLUSION: These results suggest that at least part of the cortical reorganization observed during very simple tasks in the earliest stage of MS occurs whether or not the efferent pathways are intact.

although it has been stated that children experience a larger increase in peak anaerobic power than in peak oxygen uptake during growth ([11][1], [12][2]), experimental data derived from in vitro and in vivo muscle measurements, blood samplings, and oxygen uptake dynamics do not provide a consensus

Magnetic resonance imaging (MRI) has considerably improved the diagnosis and monitoring of multiple sclerosis (MS). Conventional MRI such as T2-weighted and gadolinium-enhanced T1-weighted sequences detect focal lesions of the white matter, damage of the blood–brain barrier, and tissue loss and inflammatory activity within lesions. However, these conventional MRI metrics lack the specificity required for characterizing the underlying pathophysiology, especially diffuse damage occurring throughout the whole central nervous system. To overcome these limitations, advanced MRI techniques have been developed to get more sensitive and specific parameters of focal and diffuse brain damage. Among these techniques, magnetization transfer imaging, diffusion MRI, functional MRI, and magnetic resonance spectroscopy are the most significant. In this article, we provide an overview of these advanced MRI techniques and their contribution to the better characterization and understanding of MS.

1878-0849 (Electronic) 1769-7212 (Linking) Case Reports Journal Article; Coffine-Siris syndrome or "fifth digit" syndrome is a multiple congenital anomaly-mental retardation syndrome with severe developmental delay, coarse facial features, hirsutism and absent fifth fingernails or toenails or fifth distal phalanges. The etiology of this syndrome remains uncertain. Here we report a stillborn male baby born from consanguineous parents who might represent a very severe form of Coffine-Siris syndrome with cardiac defect and multiple brain malformations including corpus callosum agenesis and Dandy Walker malformation. To the best of our knowledge, it is the first case leading to intrauterine death. Karyotype and array comparative genomic hybridization were normal; these results give additional support to mendelian inheritance for this syndrome. In our family, the most likely mode of inheritance is autosomal recessive and the recurrence is probably as high as 25%.

1095-9572 (Electronic) 1053-8119 (Linking) Journal Article Research Support, N.I.H., Extramural; While several studies have shown the benefit of cardiac gating in diffusion MRI with single-shot EPI acquisition, cardiac gating is still not commonly used. This is probably because it requires additional time and many investigators may not be convinced that cardiac gating is worth the extra effort. Here, we tested a clinically feasible protocol with a minimal increase in scan time, and quantified the effect of cardiac gating under partial or full Fourier acquisition. Eight volunteers were scanned on a 3 T scanner with a SENSE 8-channel head coil. Diffusion-weighted, single-shot spin-echo EPI images were acquired along 32 gradient directions, with or without cardiac gating and with partial or full Fourier acquisition. Vectorcardiography (VCG) was used to trigger acquisition at a minimum delay (30 ms). The uncertainties of DTI derived parameters were estimated using residual bootstrap. With partial Fourier, cardiac gating reduced the uncertainties, and better efficiency in reducing DTI parameter variability was also achieved even allowing for the increase in total scan time. For full Fourier acquisition, minimum time gating slightly decreased the uncertainties but the efficiency was worse. A minimum trigger delay might not be the optimal scheme to avoid the majority of systole but it allows clinically acceptable scan times. We have demonstrated that cardiac gating, especially of partial Fourier acquisitions, can reduce the uncertainties of DTI derived parameters in a time-efficient manner.

1773-0597 (Electronic) 0181-5512 (Linking) Journal article; INTRODUCTION: Congenital nystagmus (CN) that is present by the age of 3 months is the most common form of nystagmus in childhood. We present a prospective study (2001-2008) in which we report imaging findings in 48 children with CN. MATERIALS AND METHODS: Twenty-six boys and 22 girls with CN underwent a complete ophthalmologic assessment and a cerebral MRI (mean age of examination under general anesthesia: 11 months). Three CN groups were formed: neurologic (n=27), sensory visual disturbance (n=14), and isolated (n=7). Cerebral MRI was interpreted by the same pediatric neuroradiologist (NG). Of the children studied, 98 % were born at term. The MRI abnormalities were classified as morphologic abnormalities (malformative or nonmalformative) and as signal abnormalities. The location of brain abnormalities was within the posterior fossa, (brain stem, cerebellum, dental nuclei, cisterna magna) and the cerebral hemisphere (white matter, perivascular spaces, midline commissures, basal ganglia). RESULTS: Pendular nystagmus was prevalent in sensory and neurologic nystagmus. On fundus examination, optic disc abnormalities were present in 70 % (19) of neurologic CN and associated with white matter abnormalities of the optic radiations in 40 % of cases. On MRI, malformative morphologic abnormalities were present in 27 cases, nonmalformative abnormalities were found in 67, and signal abnormalities in 68. Within the brain stem, signal abnormalities were found as a cockade appearance of the posterior pons in the reticular regions (neurologic n=14, sensory n=6, isolated n=3). Other bright (most frequent) signal abnormalities were found within the dentate nuclei of the posterior fossa (neurologic n=10, sensory n=3, isolated n=3) and the cerebral white matter (neurologic n=17, sensory n=7, isolated n=5) of which 24 (neurologic n=15, sensory n=5, isolated n=4) involved the optic radiations. Most of these abnormalities were related and were seen most frequently in neurologic nystagmus. The most frequent association was signal abnormalities of the white matter, ventricular dilatation, and dilatation of the perivascular spaces (60.4 %) (neurologic n=13, sensory n=6). CONCLUSION: This study showed the fundamental contribution of the cerebral MRI in CN. Cerebral abnormalities were found at the pathways for ocular motility, particularly at the saccadic pathways.

In a 6-month, placebo-controlled trial, oral fingolimod (FTY720) 1.25 or 5.0 mg, once daily, significantly reduced MRI inflammatory activity and annualized relapse rate compared with placebo in patients with relapsing multiple sclerosis (MS). The objectives were to monitor the 36-month, interim efficacy and safety results of the ongoing extension of this study. In the extension (months 7—36), placebo-treated patients were re-randomized to either dose of fingolimod; fingolimod-treated patients continued at the same dose. During months 15—24, all patients receiving fingolimod 5.0 mg switched to 1.25 mg. Of the 250 patients who entered the extension study, 173 (69%) continued to month 36. Most patients were free from gadolinium-enhanced lesions (88—89%) or new T2 lesions (70—78%) at month 36. Patients receiving continuous fingolimod treatment had sustained low annualized relapse rates of 0.20—0.21, and 68—73% remained relapse-free at month 36. Over 36 months, nasopharyngitis (34%), headache (30%), fatigue (19%) and influenza (18%) were the most commonly reported adverse events. Pulmonary function remained stable and blood pressure was stable after an initial increase (3—5 mmHg) during the first 6 months of fingolimod treatment; serious adverse events included infections and skin cancer. The low MRI and clinical disease activity at 6 months were maintained at 36 months with fingolimod, which was generally well tolerated by most patients. The efficacy and safety of oral fingolimod are being further evaluated in a large phase III MS study programme.

1477-0970 (Electronic) 1352-4585 (Linking) Journal Article; This study was performed to assess the temporal evolution of damage within lesions and the normal-appearing white matter, measured using frequent magnetization transfer (MT) MRI, in relapsing-remitting multiple sclerosis (RRMS). The relationship of MT ratio (MTR) changes with measures of lesion burden, and the sample sizes needed to demonstrate a treatment effect on MTR metrics in placebo-controlled MS trials were also investigated. Bimonthly brain conventional and MT MRI scans were acquired from 42 patients with RRMS enrolled in the placebo arm of a 14-month, double-blind trial. Longitudinal MRI changes were evaluated using a random effect linear model accounting for repeated measures, and adjusted for centre effects. The Expanded Disability Status Scale (EDSS) score remained stable over the study period. A weak, but not statistically significant, decrease over time was detected for normal-appearing brain tissue (NABT) average MTR (-0.02% per visit; p = 0.14), and MTR peak height (-0.15 per visit; p = 0.17), while average lesion MTR showed a significant decrease over the study period (-0.07% per visit; p = 0.03). At each visit, all MTR variables were significantly correlated with T2 lesion volume (LV) (average coefficients of correlation ranging from -0.54 to -0.28, and p-values from

1875-8908 (Electronic) 1387-2877 (Linking) Journal Article Research Support, Non-U.S. Gov't; In the early stages of Alzheimer's disease (AD), neurofibrillary tangles develop in the mesial temporal lobe (MTL), first in the anterior subhippocampal (perirhinal/entorhinal) cortex and then in the hippocampal formation. This region plays a key role in visualrecognition memory (VRM). VRM has been reported to be impaired in patients with amnestic mild cognitive impairment (aMCI). The aim of the present study was to determine if an impairment of VRM is associated with metabolic changes in the MTL using magnetic resonance spectroscopic imaging and if evaluating VRM can contribute to the early diagnosis of AD. 28 patients with aMCI and 28 controls underwent a full neuropsychological assessment including an evaluation of VRM using the DMS48. NAA/mIno ratios, reduced in patients with AD and associated with the severity of pathological changes, were determined in the MTL. aMCI-patients were further divided into two subgroups according to their VRM performance. aMCI-patients showed decreased NAA/mIno levels in the right hippocampus compared with controls. aMCI-patients with impaired VRM showed decreased NAA/mIno ratios in the MTL bilaterally, including a region that sampled the left anterior subhippocampal cortex, compared to controls. No changes were found in aMCI patients with normal VRM. Performance on the DMS48 correlated with NAA/mIno levels in the anterior MTL. Clinical 6-year follow-up data (available for 78.6% of the aMCI-patients) indicates that impaired performance on the DMS48 could predict conversion to AD with a sensitivity and specificity of 81.8%. These findings provide further evidence that impaired VRM, as a hallmark of MTL dysfunction, may contribute to the early diagnosis of AD.

0968-5243 (Print) 0968-5243 (Linking) Editorial Introductory Journal Article

1468-6244 (Electronic) 0022-2593 (Linking) Journal Article Research Support, Non-U.S. Gov't; BACKGROUND: Malformations of cortical development are not rare and cause a wide spectrum of neurological diseases based on the affected region in the cerebral cortex. A significant proportion of these malformations could have a genetic basis. However, genetic studies are limited because most cases are sporadic and mendelian forms are rare. METHODS: In order to identify new genetic causes in patients presenting defects of cortical organisation, array based comparative genomic hybridisation was performed in a cohort of 100 sporadic cases with various types of cortical malformations in search for inframicroscopic chromosomal rearrangements. RESULTS: In one patient presenting with periventricular nodular heterotopias and pronounced corpus callosum hypoplasia, a small (400 kb) 17p13.3 deletion involving the YWHAE gene was identified. It is shown that YWHAE is the only brain expressed gene in the deleted region and that the other genes in the interval are unlikely to contribute to the brain malformation phenotype of this patient. CONCLUSION: Most 17p13.3 deletions reported to date are large, such as the deletions causing Miller-Dieker syndrome, and involve several genes implicated in various steps of brain development. Haploinsufficiency of the mouse orthologue of YWHAE causes a defect of neuronal migration. However, the human counterpart of this phenotype was not known. The case described here represents the smallest reported deletion involving the YWHAE gene and could represent the human counterpart of the abnormal cortical organisation phenotype presented by the Ywhae heterozygous knockout mouse.

1533-4406 (Electronic) 0028-4793 (Linking) Comparative Study Journal Article Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't; BACKGROUND: Fingolimod (FTY720), a sphingosine-1-phosphate-receptor modulator that prevents lymphocyte egress from lymph nodes, showed clinical efficacy and improvement on imaging in a phase 2 study involving patients with multiple sclerosis. METHODS: In this 12-month, double-blind, double-dummy study, we randomly assigned 1292 patients with relapsing-remitting multiple sclerosis who had a recent history of at least one relapse to receive either oral fingolimod at a daily dose of either 1.25 or 0.5 mg or intramuscular interferon beta-1a (an established therapy for multiple sclerosis) at a weekly dose of 30 microg. The primary end point was the annualized relapse rate. Key secondary end points were the number of new or enlarged lesions on T(2)-weighted magnetic resonance imaging (MRI) scans at 12 months and progression of disability that was sustained for at least 3 months. RESULTS: A total of 1153 patients (89%) completed the study. The annualized relapse rate was significantly lower in both groups receiving fingolimod--0.20 (95% confidence interval [CI], 0.16 to 0.26) in the 1.25-mg group and 0.16 (95% CI, 0.12 to 0.21) in the 0.5-mg group--than in the interferon group (0.33; 95% CI, 0.26 to 0.42; P

1525-5069 (Electronic) 1525-5050 (Linking) Journal Article Research Support, Non-U.S. Gov't; In addition to the hippocampus, the entorhinal/perirhinal cortices are often involved in temporal lobe epilepsy (TLE). It has been proposed that these anterior parahippocampal structures play a key role in recognition memory. We studied the voxel-based PET correlation between number of correctly recognized targets in a new recognition memory paradigm and interictal cerebral metabolic rate for glucose, in 15 patients with TLE with hippocampal sclerosis. In comparison to healthy subjects, patients had decreased recognition of targets (P0.18, Spearman's rank test). These findings highlight the preferential involvement of entorhinal/perirhinal cortices in recognition memory in patients with TLE, and suggest that recognition memory paradigms may be useful in assessing anterior parahippocampal functional status in TLE.

0028-3770 (Print) 0028-3770 (Linking) English Abstract Journal Article; AIM: Without precise international recommendations, despite the advances of the ISUAA study, the superiority of microsurgery or endovascular treatment for unruptured intracranial aneurysm (UIA) over the natural history of this disease has not been proved. In this context, the authors evaluate their experience with the aim of assessing the results and risks of the different therapeutics and comparing them with the natural risk of this disease. MATERIAL AND METHOD: From January 1993 to July 2000, 79 patients harboring 110 UIAs were treated. These patients were divided retrospectively into two groups. Group A included 45 operated patients. Group B included 37 patients treated with endovascular coiling. The therapeutic choice was not randomized and was approved by a multidisciplinary neurovascular staff. RESULTS: The two populations were homogeneous in terms of age and sex. In group A, 12 patients presented early complications (26.6 %), with one death. In group B, 15.6 % of the patients presented an ischemic complication. After 1 year of follow-up, morbidity was 11.4 % in group A and 4.8 % for group B. Angiography found a partial recanalization in 12.5 % of the operated patients and in 33 % of the patients treated with endovascular coiling. DISCUSSION: Many factors are involved in the therapeutic decision: UIA location and size and individual risks. Progress in both surgery and interventional neuroradiology has led to good results conforming with the data reported in the literature but does not demonstrate the superiority of one technique over another.

1095-9572 (Electronic) 1053-8119 (Linking) Journal Article Research Support, Non-U.S. Gov't; RATIONALE: Reproducible direct measurement of neuronal electrical activity using MRI signal changes due to local magnetic field perturbations would represent a step change in neuroimaging methods. While some previous studies using experiments based on evoked and spontaneous activity provided encouraging results no clear demonstration of neuronal current-related MR changes in the human brain has emerged to date. The availability of simultaneously acquired EEG-fMRI in patients with frequent interictal epileptic discharges (IED), which have significantly greater amplitude than evoked potentials, offers the opportunity to further investigate the phenomenon. METHODS: We re-analysed simultaneously acquired EEG-fMRI data in 6 epilepsy patients with very frequent focal IED and a well-localised generator. A model of MRI signal changes due to fast activity and BOLD signal changes was used to identify fast MR signal changes, potentially directly reflecting neuronal activity. Simultaneously-acquired EEG allowed the comparison of electrical source localisation (ESI), clinical epilepsy localisation and BOLD signal changes with the fast MR signal changes. RESULTS: Clusters of IED-related fast MR signal change were observed in all cases. Spatial correspondence between the IED-related fast MR, BOLD, ESI clusters and irritative zone (IZ) was observed in one slice of a single dataset. The other IED-related fast MR clusters were remote from electro-clinically determined generators of interictal activity. The sign and magnitude of the fast MR signal changes varied across regions and subjects. CONCLUSION: The observed fast MR changes cannot be confidently attributed to the direct effect of neuronal currents due to lack of spatial concordance with generators of interictal activity, IED-related BOLD clusters and ESI estimates.

0006-3002 (Print) 0006-3002 (Linking) Journal Article Research Support, Non-U.S. Gov't Review; Organisation of mitochondrial metabolism is a quintessential example of a complex dissipative system which can display dynamic instabilities. Several findings have indicated that the conditions inducing instabilities are within the physiological range and that mild perturbations could elicit oscillations. Different mathematical models have been put forth in order to explain the genesis of oscillations in energy metabolism. One model considers mitochondria as an organised network of oscillators and indicates that communication between mitochondria involves mitochondrial reactive oxygen species (ROS) production acting as synchronisers of the energy status of the whole population of mitochondria. An alternative model proposes that extramitochondrial pH variations could lead to mitochondrial oscillations. Oscillatory phenomena in energy metabolism have also been investigated in vivo on the basis of 31P magnetic resonance spectroscopy (MRS) measurements of phosphocreatine post-exercise recovery in human and animal skeletal muscle. The corresponding results provide experimental evidences about the role exerted by cytosolic pH on oscillations. Finally a new simple non-linear mathematical model describing the overall chemical reaction of phosphocreatine recovery predicting oscillatory recovery pattern under certain experimental conditions is presented and discussed in the light of the experimental results reported so far.

1520-6882 (Electronic) 0003-2700 (Linking) Journal Article Research Support, Non-U.S. Gov't; (31)P NMR spectroscopy is known to be a fast and accurate method for analyzing phospholipid extracts from biological samples without prior separation. However, the number of phospholipid classes and subclasses that can be quantitated separately in (31)P NMR spectra of tissue extracts is critically dependent on a variety of experimental conditions. For solvent systems resulting in the formation of two phases, the effects of varying water and methanol content on chemical shift and line width of phospholipid signals have been previously determined. However, little attention has been paid to the influence that other extract components may exert on signal separation. We present, for the first time, a systematic and comprehensive study of (31)P NMR chemical shift as a function of four experimental parameters: (i) extract concentration, (ii) concentration of chelating agent, (iii) pH value of the aqueous component of the solvent system, and (iv) temperature of the NMR measurement. This multiparametric study provides methodological guidelines for predictable and reproducible manipulation of (31)P NMR spectra of brain phospholipids. It also provides a database for rational and efficient optimization of phospholipid spectra from other body tissues, cultured cells, and phospholipid-containing biofluids.

1769-664X (Electronic) 0929-693X (Linking) Journal Article Review

1769-664X (Electronic) 0929-693X (Linking) English Abstract Journal Article; PURPOSE: Morphologic abnormalities of the hippocampal formations (MAHF) are more frequently observed in magnetic resonance imaging (MRI). We wished to specify the types of disorders associated with these malformations based on a retrospective case series by studying the language of the children presenting these abnormalities. PATIENTS AND METHODS: From the data of all the MRIs taken in the neuroradiology ward of our center over 16 months in patients under 18 years of age, we retrospectively selected the children with an MAHF, isolated or associated with other malformations. The MAHFs were defined and described according to criteria of shape or orientation defects of the hippocampal formations. We studied the files of the patients with isolated MAHF again. Those whose clinical presentation was compatible with language assessment were tested in a prospective approach. RESULTS: Out of 2208 MRIs from 1 January 2007 to 30 April 2008, 96 (4.3%) showed an MAHF, including 61 (64%) boys and 35 (36%) girls, aged from 2 months to 17 years. Eighty-two (85%) had associated abnormalities, mainly including cerebral atrophy, corpus callosum agenesis or defect, and abnormal ventricular frontal horns. Fourteen (15%) had an isolated MAHF: 2 on the left hemisphere, 2 on the right hemisphere, and 10 on both. Of these 14, 9 were compatible with language assessment. From the test results, we divided these children into 2 groups, depending on the type and severity of the impairment. Four had very serious language disorders as part of mental retardation or autistic disorders; 4 others had language disorders predominantly in expression and phonology, with weak to pathological visual memory. This study showed no potential relation between the lateralization of MAHF and language disorders, nor between the existence of epilepsy and the severity of the language disorders. Of these 14 children, 9 had behavior and autism spectrum disorders and 7 were epileptic. CONCLUSION: Even though language disorders are often part of a larger deficiency presentation, the results we obtained suggest that isolated MAHFs are not only causes of amnestic disorders, but they could also directly underlie language disorders, particularly in expression.

1520-6882 (Electronic) 0003-2700 (Linking) Journal Article Research Support, Non-U.S. Gov't; The quality of NMR spectra in general and of spectra to be used for analysis of compound mixtures in particular is essentially defined by two basic parameters: signal-to-noise ratio and spectral resolution. The latter is determined by signal dispersion (chemical shift differences) and line widths. The present study focuses on multiparametric optimization of spectral resolution in (31)P NMR spectra of phospholipids from brain tissue extracts. This report presents, for the first time, a systematic and comprehensive study of phospholipid (31)P NMR line widths as a function of four experimental parameters: (i) extract concentration, (ii) concentration of a chelating agent, (iii) pH of the aqueous component of the solvent system, and (iv) temperature of the NMR measurement. Theoretical underpinnings of observed line width variations (transversal relaxation effects) are briefly discussed. In conjunction with an analogous, concurrently published report on chemical shift effects in the same tissue extract system, this multiparametric line width study provides a complete set of methodological guidelines for (i) generating well-defined tissue extracts, and (ii) choosing matched and optimized measurement conditions for highly reproducible and well-resolved (31)P NMR spectra of brain phospholipids. This study also offers a comprehensive database and a strategy for rational and efficient optimization of phospholipid spectra from other tissue extracts.

1873-5894 (Electronic) 0730-725X (Linking) Journal Article Research Support, Non-U.S. Gov't; BACKGROUND: Acute symptomatic inflammation is a main feature of multiple sclerosis but pathophysiological processes underlying total or partial recovery are poorly understood. OBJECTIVE: To characterize in vivo these processes at molecular, structural and functional levels using multimodal MR methods. METHODS: A neuroimaging 3-year follow-up (Weeks 0, 3, 11, 29, 59 and 169) was conducted on a 41-year-old woman presenting at baseline with a large acute demyelinating lesion of multiple sclerosis. Conventional magnetic resonance imaging (MRI), magnetization transfer imaging, diffusion-weighted imaging, functional MRI and magnetic resonance spectroscopy were conducted at 1.5 T. RESULTS: Patient presenting with subacute left hemiplegia recovered progressively (expended disability status scale 7 to 5.5). The MR exploration demonstrated structural functional and metabolic impairments at baseline. Despite restoration of the blood brain barrier integrity, high lactate levels persisted for several weeks concomitant with glial activation. Slow and progressive structural and metabolic restorations occurred from baseline to W169 (lesion volume -64%; apparent diffusion coefficient -14.7%, magnetization transfer ratio +14%, choline -51%, lipids -78%, N-acetylaspartate +77%) while functionality of the motor system recovered. CONCLUSIONS: Multimodal MRI/MRS evidenced long-term dynamics recovery processes involving tissue repair, glial activation, recovery of neuronal function and functional systems. This may impact on customized rehabilitation strategies generally focused on the first months following the onset of symptoms.

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Investigations of training effects on exercise energy cost have yielded conflicting results. The purpose of the present study was to compare quadriceps energy cost and oxidative capacity between endurance-trained and sedentary subjects during a heavy dynamic knee extension exercise. We quantified the rates of ATP turnover from oxidative and anaerobic pathways with (31)P-MRS, and we measured simultaneously pulmonary oxygen uptake in order to assess both total ATP production [i.e., energy cost (EC)] and O(2) consumption (O(2) cost) scaled to power output. Seven sedentary (SED) and seven endurance-trained (TRA) subjects performed a dynamic standardized rest-exercise-recovery protocol at an exercise intensity corresponding to 35% of maximal voluntary contraction. We showed that during a dynamic heavy exercise, the O(2) cost and EC were similar in the SED and endurance-trained groups. For a given EC, endurance-trained subjects exhibited a higher relative mitochondrial contribution to ATP production at the muscle level (84 +/- 12% in TRA and 57 +/- 12% in SED; P0.01) whereas the anaerobic contribution was reduced (18 +/- 12% in TRA and 44 +/- 11% in SED; P0.01). Our results obtained in vivo illustrate that on the one hand the beneficial effects of endurance training are not related to any reduction in EC or O(2) cost and on the other hand that this similar EC was linked to a change regarding the contribution of anaerobic and oxidative processes to energy production, i.e., a greater aerobic energy contribution associated with a concomitant reduction of the anaerobic energy supply.

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International audience

Recent neuropathologic research suggests thalamic involvement in sporadic Creutzfeldt-Jakob disease (sCJD), which has been disregarded in imaging studies. Diffusion-weighted (DW) MR imaging has the highest sensitivity for the detection of signal intensity (SI) abnormalities in CJD. We hypothesized that pathologic changes in the thalamus in sCJD can be detected by using a subtle analysis of DW MR imaging.Six sCJD patients and nine healthy controls were examined with a 1.5-T system by using DW single-shot spin-echo echo planar (b = 0, 1000 s/mm(2)), T2-weighted turbo spin-echo, and fluid-attenuated inversion recovery sequences. One patient was examined serially (3, 4, and 8 months after onset of symptoms). MR images were reviewed for SI changes in the striatum, hippocampus, mediodorsal thalamic nucleus (MD), and pulvinar thalami. Apparent diffusion coefficients (ADCs) were measured in these areas.All sCJD patients showed increased SI on DW images in the striatum bilaterally. ADCs in these areas were significantly reduced. Four of six sCJD patients showed increased SI on DW images in the pulvinar thalami, whereas ADCs were significantly reduced in all patients (mean ADC +/- SEM: in patients with SI changes, 701 +/- 38; in patients without SI changes, 684 +/- 37; in controls, 853 +/- 15 [P.0001]). No patient showed SI changes in the MD on DW images, whereas ADCs were significantly reduced in all (664 +/- 28 as compared with 800 +/- 24 in controls [P =.0011]). Serial measurements in one sCJD patient showed ADC reduction in the pulvinar thalami preceding the SI changes on DW images.A quantitative analysis of DW images with ADC measurements shows slight MR imaging changes in the thalamus in sCJD when abnormal SI may not be present.