Which prior knowledge? Quantification of in vivo brain 13C MR spectra following 13C glucose infusion using AMARES.

The recent developments in high magnetic field 13C magnetic resonance spectroscopy with improved localization and shimming techniques have led to important gains in sensitivity and spectral resolution of 13C in vivo spectra in the rodent brain, enabling the separation of several 13C isotopomers of glutamate and glutamine. In this context, the assumptions used in spectral quantification might have a significant impact on the determination of the 13C concentrations and the related metabolic fluxes. In this study, the time domain spectral quantification algorithm AMARES (advanced method for accurate, robust and efficient spectral fitting) was applied to 13 C magnetic resonance spectroscopy spectra acquired in the rat brain at 9.4 T, following infusion of [1,6-(13)C2 ] glucose. Using both Monte Carlo simulations and in vivo data, the goal of this work was: (1) to validate the quantification of in vivo 13C isotopomers using AMARES; (2) to assess the impact of the prior knowledge on the quantification of in vivo 13C isotopomers using AMARES; (3) to compare AMARES and LCModel (linear combination of model spectra) for the quantification of in vivo 13C spectra. AMARES led to accurate and reliable 13C spectral quantification similar to those obtained using LCModel, when the frequency shifts, J-coupling constants and phase patterns of the different 13C isotopomers were included as prior knowledge in the analysis.

Central and Cortical Gray Mater Segmentation of Magnetic Resonance Images of the Fetal Brain

Motivation. The study of human brain development in itsearly stage is today possible thanks to in vivo fetalmagnetic resonance imaging (MRI) techniques. Aquantitative analysis of fetal cortical surfacerepresents a new approach which can be used as a markerof the cerebral maturation (as gyration) and also forstudying central nervous system pathologies [1]. However,this quantitative approach is a major challenge forseveral reasons. First, movement of the fetus inside theamniotic cavity requires very fast MRI sequences tominimize motion artifacts, resulting in a poor spatialresolution and/or lower SNR. Second, due to the ongoingmyelination and cortical maturation, the appearance ofthe developing brain differs very much from thehomogenous tissue types found in adults. Third, due tolow resolution, fetal MR images considerably suffer ofpartial volume (PV) effect, sometimes in large areas.Today extensive efforts are made to deal with thereconstruction of high resolution 3D fetal volumes[2,3,4] to cope with intra-volume motion and low SNR.However, few studies exist related to the automatedsegmentation of MR fetal imaging. [5] and [6] work on thesegmentation of specific areas of the fetal brain such asposterior fossa, brainstem or germinal matrix. Firstattempt for automated brain tissue segmentation has beenpresented in [7] and in our previous work [8]. Bothmethods apply the Expectation-Maximization Markov RandomField (EM-MRF) framework but contrary to [7] we do notneed from any anatomical atlas prior. Data set &Methods. Prenatal MR imaging was performed with a 1-Tsystem (GE Medical Systems, Milwaukee) using single shotfast spin echo (ssFSE) sequences (TR 7000 ms, TE 180 ms,FOV 40 x 40 cm, slice thickness 5.4mm, in plane spatialresolution 1.09mm). Each fetus has 6 axial volumes(around 15 slices per volume), each of them acquired inabout 1 min. Each volume is shifted by 1 mm with respectto the previous one. Gestational age (GA) ranges from 29to 32 weeks. Mother is under sedation. Each volume ismanually segmented to extract fetal brain fromsurrounding maternal tissues. Then, in-homogeneityintensity correction is performed using [9] and linearintensity normalization is performed to have intensityvalues that range from 0 to 255. Note that due tointra-tissue variability of developing brain someintensity variability still remains. For each fetus, ahigh spatial resolution image of isotropic voxel size of1.09 mm is created applying [2] and using B-splines forthe scattered data interpolation [10] (see Fig. 1). Then,basal ganglia (BS) segmentation is performed on thissuper reconstructed volume. Active contour framework witha Level Set (LS) implementation is used. Our LS follows aslightly different formulation from well-known Chan-Vese[11] formulation. In our case, the LS evolves forcing themean of the inside of the curve to be the mean intensityof basal ganglia. Moreover, we add local spatial priorthrough a probabilistic map created by fitting anellipsoid onto the basal ganglia region. Some userinteraction is needed to set the mean intensity of BG(green dots in Fig. 2) and the initial fitting points forthe probabilistic prior map (blue points in Fig. 2). Oncebasal ganglia are removed from the image, brain tissuesegmentation is performed as described in [8]. Results.The case study presented here has 29 weeks of GA. Thehigh resolution reconstructed volume is presented in Fig.1. The steps of BG segmentation are shown in Fig. 2.Overlap in comparison with manual segmentation isquantified by the Dice similarity index (DSI) equal to0.829 (values above 0.7 are considered a very goodagreement). Such BG segmentation has been applied on 3other subjects ranging for 29 to 32 GA and the DSI hasbeen of 0.856, 0.794 and 0.785. Our segmentation of theinner (red and blue contours) and outer cortical surface(green contour) is presented in Fig. 3. Finally, torefine the results we include our WM segmentation in theFreesurfer software [12] and some manual corrections toobtain Fig.4. Discussion. Precise cortical surfaceextraction of fetal brain is needed for quantitativestudies of early human brain development. Our workcombines the well known statistical classificationframework with the active contour segmentation forcentral gray mater extraction. A main advantage of thepresented procedure for fetal brain surface extraction isthat we do not include any spatial prior coming fromanatomical atlases. The results presented here arepreliminary but promising. Our efforts are now in testingsuch approach on a wider range of gestational ages thatwe will include in the final version of this work andstudying as well its generalization to different scannersand different type of MRI sequences. References. [1]Guibaud, Prenatal Diagnosis 29(4) (2009). [2] Rousseau,Acad. Rad. 13(9), 2006, [3] Jiang, IEEE TMI 2007. [4]Warfield IADB, MICCAI 2009. [5] Claude, IEEE Trans. Bio.Eng. 51(4) (2004). [6] Habas, MICCAI (Pt. 1) 2008. [7]Bertelsen, ISMRM 2009 [8] Bach Cuadra, IADB, MICCAI 2009.[9] Styner, IEEE TMI 19(39 (2000). [10] Lee, IEEE Trans.Visual. And Comp. Graph. 3(3), 1997, [11] Chan, IEEETrans. Img. Proc, 10(2), 2001 [12] Freesurfer,http://surfer.nmr.mgh.harvard.edu.

MR spectroscopy of the human brain with enhanced signal intensity at ultrashort echo times on a clinical platform at 3T and 7T.

Recently, the spin-echo full-intensity acquired localized (SPECIAL) spectroscopy technique was proposed to unite the advantages of short TEs on the order of milliseconds (ms) with full sensitivity and applied to in vivo rat brain. In the present study, SPECIAL was adapted and optimized for use on a clinical platform at 3T and 7T by combining interleaved water suppression (WS) and outer volume saturation (OVS), optimized sequence timing, and improved shimming using FASTMAP. High-quality single voxel spectra of human brain were acquired at TEs below or equal to 6 ms on a clinical 3T and 7T system for six volunteers. Narrow linewidths (6.6 +/- 0.6 Hz at 3T and 12.1 +/- 1.0 Hz at 7T for water) and the high signal-to-noise ratio (SNR) of the artifact-free spectra enabled the quantification of a neurochemical profile consisting of 18 metabolites with Cramér-Rao lower bounds (CRLBs) below 20% at both field strengths. The enhanced sensitivity and increased spectral resolution at 7T compared to 3T allowed a two-fold reduction in scan time, an increased precision of quantification for 12 metabolites, and the additional quantification of lactate with CRLB below 20%. Improved sensitivity at 7T was also demonstrated by a 1.7-fold increase in average SNR (= peak height/root mean square [RMS]-of-noise) per unit-time.

Sleep, metabolism and aging

Aging is a multidimensional process of physical, psychological, and social changes. Understanding how we sleep and how this dynamic process evolves across life span will help to identify normal developmental aspects of sleep over time and to create strategies to increase awareness of sleep disturbances and their early management. In normal sleepers from HypnoLaus cohort, we evaluated the effects of age and gender on both subjective and objective sleep measurements. Our results indicate that normal aging is not accompanied by sleep complaints, and when they exist suggest the presence of underlying comorbidities. Polysomnographic data revealed that slow wave sleep was more affected with age in men, and age affected differently NREM and REM spectral power densities. Both sleep structure and spectral analysis profiles may constitute standards to delineate pathological changes in sleep, both for aging women and men. Another important aspect in the management of sleep and its disorders is a detailed characterization of sleep-inducing medications. Gamma-hydroxybutyrate (GHB) is an inhibitory neurotransmitter derivative of GABA, but its mode of action and the range of effects are not well understood. Several properties, as growth hormone stimulation in humans and the development of weight loss in treated patients suggest an unexplored metabolic effect. In different experiments we assessed the effects of acute, short term and chronic GHB administration on central (cerebral cortex) and peripheral (liver) biochemical processes involved in the metabolism of the drug, as well as the effects of the drug on metabolism in C57BL/6J, GABAB knock-out and obese (ob/ob) mice. We showed that GHB treatment affects weight gain in C57BL/6J and GABAB knock-out mice. Metabolomic analysis indicated large central and peripheral metabolic changes induced by GHB with important relevance to its therapeutic use. -- Le vieillissement est un processus multidimensionnel accompagné par de multiples changements dans les domaines physique, psychologique et social. Comprendre comment nous dormons et comment ce processus dynamique évolue sur la durée de vie nous aidera à identifier les aspects normaux du développement du sommeil au fil du temps, et à créer des stratégies pour accroître la connaissance et compréhension des troubles du sommeil et leur prise en charge précoce. Chez les sujets normaux de la cohorte HypnoLaus nous avons évalué les effets de l'âge et du sexe sur les mesures subjectives et objectives du sommeil. Nos résultats indiquent que le vieillissement normal ne s'accompagne pas de troubles du sommeil, et quand ils existent ceux-ci suggèrent la présence de comorbidités sous-jacentes. Les données polysomnographiques ont révélé que le sommeil profond était plus affecté avec l'âge chez les hommes. De plus, nous avons montré comment l'âge modifie la composition spectrale du sommeil lent et paradoxal. La structure du sommeil et les profils d'analyse spectrale peuvent donc constituer des standards permettant de définir les changements pathologiques du sommeil chez les personnes âgées. Parmi les aspects importants de la gestion du sommeil et de ses troubles, la caractérisation détaillée des médicaments hypnotiques utilisés est essentielle. L'acide gamma-hydroxybutyrique (GHB) est un acide gras à courte chaîne dérivé du GABA, principal neurotransmetteur inhibiteur du cerveau, mais son mode d'action et tous ses effets sont toujours largement méconnus. Plusieurs propriétés, comme la stimulation de la sécrétion de l'hormone de croissance chez l'homme et le développement d'une perte de poids chez les patients traités suggèrent un effet métabolique inexploré. Dans différentes expériences, nous avons évalué les effets d'une exposition aiguë, à court terme et chronique de GHB sur les processus biochimiques centraux (cortex cérébral) et périphériques (foie) impliqués dans le métabolisme du médicament. Nous avons aussi évalué les effets du médicament sur le métabolisme des souris C57BL/6J, GABAB KO et obèses (ob/ob). Nos résultats ont montré que le GHB diminue le gain de poids chez les souris C57BL/6J et GABAB KO. L'analyse métabolomique a indiqué des changements importants induits par GHB au niveau central et périphérique, et ces effets sont importants pour son utilisation thérapeutique.

Electroencephalogram paroxysmal theta characterizes cataplexy in mice and children.

Astute control of brain activity states is critical for adaptive behaviours and survival. In mammals and birds, electroencephalographic recordings reveal alternating states of wakefulness, slow wave sleep and paradoxical sleep (or rapid eye movement sleep). This control is profoundly impaired in narcolepsy with cataplexy, a disease resulting from the loss of orexin/hypocretin neurotransmitter signalling in the brain. Narcolepsy with cataplexy is characterized by irresistible bouts of sleep during the day, sleep fragmentation during the night and episodes of cataplexy, a sudden loss of muscle tone while awake and experiencing emotions. The neural mechanisms underlying cataplexy are unknown, but commonly thought to involve those of rapid eye movement-sleep atonia, and cataplexy typically is considered as a rapid eye movement sleep disorder. Here we reassess cataplexy in hypocretin (Hcrt, also known as orexin) gene knockout mice. Using a novel video/electroencephalogram double-blind scoring method, we show that cataplexy is not a state per se, as believed previously, but a dynamic, multi-phased process involving a reproducible progression of states. A knockout-specific state and a stereotypical paroxysmal event were introduced to account for signals and electroencephalogram spectral characteristics not seen in wild-type littermates. Cataplexy almost invariably started with a brief phase of wake-like electroencephalogram, followed by a phase featuring high-amplitude irregular theta oscillations, defining an activity profile distinct from paradoxical sleep, referred to as cataplexy-associated state and in the course of which 1.5-2 s high-amplitude, highly regular, hypersynchronous paroxysmal theta bursts (∼7 Hz) occurred. In contrast to cataplexy onset, exit from cataplexy did not show a predictable sequence of activities. Altogether, these data contradict the hypothesis that cataplexy is a state similar to paradoxical sleep, even if long cataplexies may evolve into paradoxical sleep. Although not exclusive to overt cataplexy, cataplexy-associated state and hypersynchronous paroxysmal theta activities are highly enriched during cataplexy in hypocretin/orexin knockout mice. Their occurrence in an independent narcolepsy mouse model, the orexin/ataxin 3 transgenic mouse, undergoing loss of orexin neurons, was confirmed. Importantly, we document for the first time similar paroxysmal theta hypersynchronies (∼4 Hz) during cataplexy in narcoleptic children. Lastly, we show by deep recordings in mice that the cataplexy-associated state and hypersynchronous paroxysmal theta activities are independent of hippocampal theta and involve the frontal cortex. Cataplexy hypersynchronous paroxysmal theta bursts may represent medial prefrontal activity, associated in humans and rodents with reward-driven motor impulse, planning and conflict monitoring.

Fast Geodesic Active Fields for Image Registration Based on Splitting and Augmented Lagrangian Approaches.

In this paper, we present an efficient numerical scheme for the recently introduced geodesic active fields (GAF) framework for geometric image registration. This framework considers the registration task as a weighted minimal surface problem. Hence, the data-term and the regularization-term are combined through multiplication in a single, parametrization invariant and geometric cost functional. The multiplicative coupling provides an intrinsic, spatially varying and data-dependent tuning of the regularization strength, and the parametrization invariance allows working with images of nonflat geometry, generally defined on any smoothly parametrizable manifold. The resulting energy-minimizing flow, however, has poor numerical properties. Here, we provide an efficient numerical scheme that uses a splitting approach; data and regularity terms are optimized over two distinct deformation fields that are constrained to be equal via an augmented Lagrangian approach. Our approach is more flexible than standard Gaussian regularization, since one can interpolate freely between isotropic Gaussian and anisotropic TV-like smoothing. In this paper, we compare the geodesic active fields method with the popular Demons method and three more recent state-of-the-art algorithms: NL-optical flow, MRF image registration, and landmark-enhanced large displacement optical flow. Thus, we can show the advantages of the proposed FastGAF method. It compares favorably against Demons, both in terms of registration speed and quality. Over the range of example applications, it also consistently produces results not far from more dedicated state-of-the-art methods, illustrating the flexibility of the proposed framework.

Different colors of light lead to different adaptation and activation as determined by high-density EEG.

Light adaptation is crucial for coping with the varying levels of ambient light. Using high-density electroencephalography (EEG), we investigated how adaptation to light of different colors affects brain responsiveness. In a within-subject design, sixteen young participants were adapted first to dim white light and then to blue, green, red, or white bright light (one color per session in a randomized order). Immediately after both dim and bright light adaptation, we presented brief light pulses and recorded event-related potentials (ERPs). We analyzed ERP response strengths and brain topographies and determined the underlying sources using electrical source imaging. Between 150 and 261ms after stimulus onset, the global field power (GFP) was higher after dim than bright light adaptation. This effect was most pronounced with red light and localized in the frontal lobe, the fusiform gyrus, the occipital lobe and the cerebellum. After bright light adaptation, within the first 100ms after light onset, stronger responses were found than after dim light adaptation for all colors except for red light. Differences between conditions were localized in the frontal lobe, the cingulate gyrus, and the cerebellum. These results indicate that very short-term EEG brain responses are influenced by prior light adaptation and the spectral quality of the light stimulus. We show that the early EEG responses are differently affected by adaptation to different colors of light which may contribute to known differences in performance and reaction times in cognitive tests.

Recurrent Macular Edema in Central Retinal Vein Occlusion Treated with Intravitreal Ranibizumab using a Modified Treat and Extend Regimen.

Background: The aim of this study was to evaluate the stability over time of the individually defined interval of intravitreal ranibizumab injection (IVR) for the treatment of recurrent macular edema (ME) in central retinal vein occlusion (CRVO). Patients and Methods: A case series of treatment naïve patients followed in the Jules Gonin Eye Hospital for macular edema due to central retinal vein occlusion is presented. Patients were treated monthly with IVR until complete absence of fluid on qualitative SD-OCT with a minimum of 5 monthly IVR. Thereafter, they were followed according to a modified treat and extend regimen (mTER). Results: Twelve eyes (12 patients) with ME due to CRVO were included. The mean follow-up period was 31.3 months. Analysis showed that best corrected visual acuity (BCVA), central macular thickness and qualitative spectral domain optical coherence tomography (SD-OCT) showed comparable results under monthly interval, after titration of an individualized interval and when performed in a series. 78 % of treating intervals were within ± 2 weeks of the first individually adjusted interval. The mean first defined interval was 4.3 weeks and the mean interval over time was 5.5 weeks (p = 0.003). There was a trend towards longer interval over time. Conclusion: The adjusted interval of retreatment of patients with ME due to CRVO showed a high stability with a trend toward longer duration over time. An mTER regimen seems to be valuable to follow patients with ME with good stabilization of VA.

Fingermark initial composition and aging using Fourier transform infrared microscopy (μ-FTIR)

This study investigated fingermark residues using Fourier transform infrared microscopy (μ- FTIR) in order to obtain fundamental information about the marks' initial composition and aging kinetics. This knowledge would be an asset for fundamental research on fingermarks, such as for dating purposes. Attenuated Total Reflection (ATR) and single-point reflection modes were tested on fresh fingermarks. ATR proved to be better suited and this mode was subsequently selected for further aging studies. Eccrine and sebaceous material was found in fresh and aged fingermarks and the spectral regions 1000-1850 cm-1 and 2700-3600 cm-1 were identified as the most informative. The impact of substrates (aluminium and glass slides) and storage conditions (storage in the light and in the dark) on fingermark aging was also studied. Chemometric analyses showed that fingermarks could be grouped according to their age regardless of the substrate when they were stored in an open box kept in an air-conditioned laboratory at around 20°C next to a window. On the contrary, when fingermarks were stored in the dark, only specimens deposited on the same substrate could be grouped by age. Thus, the substrate appeared to influence aging of fingermarks in the dark. Furthermore, PLS regression analyses were conducted in order to study the possibility of modelling fingermark aging for potential fingermark dating applications. The resulting models showed an overall precision of ±3 days and clearly demonstrated their capability to differentiate older fingermarks (20 and 34-days old) from newer ones (1, 3, 7 and 9-days old) regardless of the substrate and lighting conditions. These results are promising from a fingermark dating perspective. Further research is required to fully validate such models and assess their robustness and limitations in uncontrolled casework conditions.

Free-breathing 3 T magnetic resonance t(2)-mapping of the heart.

OBJECTIVES: This study sought to establish an accurate and reproducible T(2)-mapping cardiac magnetic resonance (CMR) methodology at 3 T and to evaluate it in healthy volunteers and patients with myocardial infarct. BACKGROUND: Myocardial edema affects the T(2) relaxation time on CMR. Therefore, T(2)-mapping has been established to characterize edema at 1.5 T. A 3 T implementation designed for longitudinal studies and aimed at guiding and monitoring therapy remains to be implemented, thoroughly characterized, and evaluated in vivo. METHODS: A free-breathing navigator-gated radial CMR pulse sequence with an adiabatic T(2) preparation module and an empirical fitting equation for T(2) quantification was optimized using numerical simulations and was validated at 3 T in a phantom study. Its reproducibility for myocardial T(2) quantification was then ascertained in healthy volunteers and improved using an external reference phantom with known T(2). In a small cohort of patients with established myocardial infarction, the local T(2) value and extent of the edematous region were determined and compared with conventional T(2)-weighted CMR and x-ray coronary angiography, where available. RESULTS: The numerical simulations and phantom study demonstrated that the empirical fitting equation is significantly more accurate for T(2) quantification than that for the more conventional exponential decay. The volunteer study consistently demonstrated a reproducibility error as low as 2 ± 1% using the external reference phantom and an average myocardial T(2) of 38.5 ± 4.5 ms. Intraobserver and interobserver variability in the volunteers were -0.04 ± 0.89 ms (p = 0.86) and -0.23 ± 0.91 ms (p = 0.87), respectively. In the infarction patients, the T(2) in edema was 62.4 ± 9.2 ms and was consistent with the x-ray angiographic findings. Simultaneously, the extent of the edematous region by T(2)-mapping correlated well with that from the T(2)-weighted images (r = 0.91). CONCLUSIONS: The new, well-characterized 3 T methodology enables robust and accurate cardiac T(2)-mapping at 3 T with high spatial resolution, while the addition of a reference phantom improves reproducibility. This technique may be well suited for longitudinal studies in patients with suspected or established heart disease.

General unknown screening procedure for the characterization of human drug metabolites: application to loratadine phase I metabolism.

This article describes the application of a recently developed general unknown screening (GUS) strategy based on LC coupled to a hybrid linear IT-triple quadrupole mass spectrometer (LC-MS/MS-LIT) for the simultaneous detection and identification of drug metabolites following in vitro incubation with human liver microsomes. The histamine H1 receptor antagonist loratadine was chosen as a model compound to demonstrate the interest of such approach, because of its previously described complex and extensive metabolism. Detection and mass spectral characterization were based on data-dependent acquisition, switching between a survey scan acquired in the ion-trapping Q3 scan mode with dynamic subtraction of background noise, and a dependent scan in the ion-trapping product ion scan mode of automatically selected parent ions. In addition, the MS(3) mode was used in a second step to confirm the structure of a few fragment ions. The sensitivity of the ion-trapping modes combined with the selectivity of the triple quadrupole modes allowed, with only one injection, the detection and identification of 17 phase I metabolites of loratadine. The GUS procedure used in this study may be applicable as a generic technique for the characterization of drug metabolites after in vitro incubation, as well as probably in vivo experiments.

Relating the permeability of quartz sands to their grain size and spectral induced polarization characteristics

Recently, Revil & Florsch proposed a novel mechanistic model based on the polarization of the Stern layer relating the permeability of granular media to their spectral induced polarization (SIP) characteristics based on the formation of polarized cells around individual grains. To explore the practical validity of this model, we compare it to pertinent laboratory measurements on samples of quartz sands with a wide range of granulometric characteristics. In particular, we measure the hydraulic and SIP characteristics of all samples both in their loose, non-compacted and compacted states, which might allow for the detection of polarization processes that are independent of the grain size. We first verify the underlying grain size/permeability relationship upon which the model of Revil & Florsch is based and then proceed to compare the observed and predicted permeability values for our samples by substituting the grain size characteristics by corresponding SIP parameters, notably the so-called Cole-Cole time constant. In doing so, we also asses the quantitative impact of an observed shift in the Cole-Cole time constant related to textural variations in the samples and observe that changes related to the compaction of the samples are not relevant for the corresponding permeability predictions. We find that the proposed model does indeed provide an adequate prediction of the overall trend of the observed permeability values, but underestimates their actual values by approximately one order-of-magnitude. This discrepancy in turn points to the potential importance of phenomena, which are currently not accounted for in the model and which tend to reduce the characteristic size of the prevailing polarization cells compared to the considered model, such as, for example, membrane polarization, contacts of double-layers of neighbouring grains, and incorrect estimation of the size of the polarized cells because of the irregularity of natural sand grains.