Multimodal MRI analysis of structural and functional networks in the human brain : application to two clinical studies : driving abilities under THC intoxication and early white matter changes in FXTAS

Les approches multimodales dans l'imagerie cérébrale non invasive sont de plus en plus considérées comme un outil indispensable pour la compréhension des différents aspects de la structure et de la fonction cérébrale. Grâce aux progrès des techniques d'acquisition des images de Resonance Magnetique et aux nouveaux outils pour le traitement des données, il est désormais possible de mesurer plusieurs paramètres sensibles aux différentes caractéristiques des tissues cérébraux. Ces progrès permettent, par exemple, d'étudier les substrats anatomiques qui sont à la base des processus cognitifs ou de discerner au niveau purement structurel les phénomènes dégénératifs et développementaux. Cette thèse met en évidence l'importance de l'utilisation d'une approche multimodale pour étudier les différents aspects de la dynamique cérébrale grâce à l'application de cette approche à deux études cliniques: l'évaluation structurelle et fonctionnelle des effets aigus du cannabis fumé chez des consommateurs réguliers et occasionnels, et l'évaluation de l'intégrité de la substance grise et blanche chez des jeunes porteurs de la prémutations du gène FMR1 à risque de développer le FXTAS (Fragile-X Tremor Ataxia Syndrome). Nous avons montré que chez les fumeurs occasionnels de cannabis, même à faible concentration du principal composant psychoactif (THC) dans le sang, la performance lors d'une tâche visuo-motrice est fortement diminuée, et qu'il y a des changements dans l'activité des trois réseaux cérébraux impliqués dans les processus cognitifs: le réseau de saillance, le réseau du contrôle exécutif, et le réseau actif par défaut (Default Mode). Les sujets ne sont pas en mesure de saisir les saillances dans l'environnement et de focaliser leur attention sur la tâche. L'augmentation de la réponse hémodynamique dans le cortex cingulaire antérieur suggère une augmentation de l'activité introspective. Une investigation des ef¬fets au niveau cérébral d'une exposition prolongée au cannabis, montre des changements persistants de la substance grise dans les régions associées à la mémoire et au traitement des émotions. Le niveau d'atrophie dans ces structures corrèle avec la consommation de cannabis au cours des trois mois précédant l'étude. Dans la deuxième étude, nous démontrons des altérations structurelles des décennies avant l'apparition du syndrome FXTAS chez des sujets jeunes, asymptomatiques, et porteurs de la prémutation du gène FMR1. Les modifications trouvées peuvent être liées à deux mécanismes différents. Les altérations dans le réseau moteur du cervelet et dans la fimbria de l'hippocampe, suggèrent un effet développemental de la prémutation. Elles incluent aussi une atrophie de la substance grise du lobule VI du cervelet et l'altération des propriétés tissulaires de la substance blanche des projections afférentes correspondantes aux pédoncules cérébelleux moyens. Les lésions diffuses de la substance blanche cérébrale peu¬vent être un marquer précoce du développement de la maladie, car elles sont liées à un phénomène dégénératif qui précède l'apparition des symptômes du FXTAS. - Multimodal brain imaging is becoming a leading tool for understanding different aspects of brain structure and function. Thanks to the advances in Magnetic Resonance imaging (MRI) acquisition schemes and data processing techniques, it is now possible to measure different parameters sensitive to different tissue characteristics. This allows for example to investigate anatomical substrates underlying cognitive processing, or to disentangle, at a pure structural level degeneration and developmental processes. This thesis highlights the importance of using a multimodal approach for investigating different aspects of brain dynamics by applying this approach to two clinical studies: functional and structural assessment of the acute effects of cannabis smoking in regular and occasional users, and grey and white matter assessment in young FMR1 premutation carriers at risk of developing FXTAS. We demonstrate that in occasional smokers cannabis smoking, even at low concentration of the main psychoactive component (THC) in the blood, strongly decrease subjects' performance on a visuo-motor tracking task, and globally alters the activity of the three brain networks involved in cognitive processing: the Salience, the Control Executive, and the Default Mode networks. Subjects are unable to capture saliences in the environment and to orient attention to the task; the increase in Hemodynamic Response in the Anterior Cingulate Cortex suggests an increase in self-oriented mental activity. A further investigation on long term exposure to cannabis, shows a persistent grey matter modification in brain regions associated with memory and affective processing. The degree of atrophy in these structures also correlates with the estimation of drug use in the three months prior the participation to the study. In the second study we demonstrate structural changes in young asymptomatic premutation carriers decades before the onset of FXTAS that might be related to two different mechanisms. Alteration of the cerebellar motor network and of the hippocampal fimbria/ fornix, may reflect a potential neurodevelopmental effect of the premutation. These include grey matter atrophy in lobule VI and modification of white matter tissue property in the corresponding afferent projections through the Middle Cerebellar Peduncles. Diffuse hemispheric white matter lesions that seem to appear closer to the onset of FXTAS and be related to a neurodegenerative phenomenon may mark the imminent onset of FXTAS.

Peritoneal Carcinomatosis in Primary Ovarian Cancer Staging: Comparison Between MDCT, MRI, and 18F-FDG PET/CT.

PURPOSE: The aim of this study was to compare multidetector CT (MDCT), MRI, and FDG PET/CT imaging for the detection of peritoneal carcinomatosis (PC) in ovarian cancer. PATIENTS AND METHODS: Fifteen women with ovarian cancer and suspected PC underwent MDCT, MRI, and FDG PET/CT, shortly before surgery. Nine abdominopelvic regions were defined according to the peritoneal cancer index. We applied lesion size scores on MDCT and MR and measured FDG PET/CT standard uptake. We blindly read MDCT, MR, and PET/CT before joint review and comparison with histopathology. Receiver operating characteristics analysis was performed. RESULTS: Ten women had PC (67%). Altogether, 135 abdominopelvic sites were compared. Multidetector CT, MRI, and FDG PET/CT had a sensitivity of 96%, 98%, and 95%, and specificity was 92%, 84%, and 96%, respectively. Corresponding receiver operating characteristics area was 0.94, 0.90, and 0.96, respectively, without any significant differences between them (P = 0.12). FDG PET/CT detected supradiaphragmatic disease in 3 women (20%) not seen by MDCT or MRI. CONCLUSIONS: Although MRI had the highest sensitivity and FDG PET/CT had the highest specificity, no significant differences were found between the 3 techniques. Thus, MDCT, as the fastest, most economical, and most widely available modality, is the examination of choice, if a stand-alone technique is required. If inconclusive, PET/CT or MRI may offer additional insights. Whole-body FDG PET/CT may be more accurate for supradiaphragmatic metastatic extension.

Prospective motion correction of 3D echo-planar imaging data for functional MRI using optical tracking.

We evaluated the performance of an optical camera based prospective motion correction (PMC) system in improving the quality of 3D echo-planar imaging functional MRI data. An optical camera and external marker were used to dynamically track the head movement of subjects during fMRI scanning. PMC was performed by using the motion information to dynamically update the sequence's RF excitation and gradient waveforms such that the field-of-view was realigned to match the subject's head movement. Task-free fMRI experiments on five healthy volunteers followed a 2×2×3 factorial design with the following factors: PMC on or off; 3.0mm or 1.5mm isotropic resolution; and no, slow, or fast head movements. Visual and motor fMRI experiments were additionally performed on one of the volunteers at 1.5mm resolution comparing PMC on vs PMC off for no and slow head movements. Metrics were developed to quantify the amount of motion as it occurred relative to k-space data acquisition. The motion quantification metric collapsed the very rich camera tracking data into one scalar value for each image volume that was strongly predictive of motion-induced artifacts. The PMC system did not introduce extraneous artifacts for the no motion conditions and improved the time series temporal signal-to-noise by 30% to 40% for all combinations of low/high resolution and slow/fast head movement relative to the standard acquisition with no prospective correction. The numbers of activated voxels (p<0.001, uncorrected) in both task-based experiments were comparable for the no motion cases and increased by 78% and 330%, respectively, for PMC on versus PMC off in the slow motion cases. The PMC system is a robust solution to decrease the motion sensitivity of multi-shot 3D EPI sequences and thereby overcome one of the main roadblocks to their widespread use in fMRI studies.

Free-running 4D whole-heart self-navigated golden angle MRI: Initial results.

PURPOSE: To test the hypothesis that both coronary anatomy and ventricular function can be assessed simultaneously using a single four-dimensional (4D) acquisition. METHODS: A free-running 4D whole-heart self-navigated acquisition incorporating a golden angle radial trajectory was implemented and tested in vivo in nine healthy adult human subjects. Coronary magnetic resonance angiography (MRA) datasets with retrospective selection of acquisition window width and position were extracted and quantitatively compared with baseline self-navigated electrocardiography (ECG) -triggered coronary MRA. From the 4D datasets, the left-ventricular end-systolic, end-diastolic volumes (ESV & EDV) and ejection fraction (EF) were computed and compared with values obtained from conventional 2D cine images. RESULTS: The 4D datasets enabled dynamic assessment of the whole heart with isotropic spatial resolution of 1.15 mm(3) . Coronary artery image quality was very similar to that of the ECG-triggered baseline scan despite some SNR penalty. A good agreement between 4D and 2D cine imaging was found for EDV, ESV, and EF. CONCLUSION: The hypothesis that both coronary anatomy and ventricular function can be assessed simultaneously in vivo has been tested positive. Retrospective and flexible acquisition window selection allows to best visualize each coronary segment at its individual time point of quiescence. Magn Reson Med, 2014. © 2014 Wiley Periodicals, Inc.

Structured sparsity for spatially coherent fibre orientation estimation in diffusion MRI.

We propose a novel formulation to solve the problem of intra-voxel reconstruction of the fibre orientation distribution function (FOD) in each voxel of the white matter of the brain from diffusion MRI data. The majority of the state-of-the-art methods in the field perform the reconstruction on a voxel-by-voxel level, promoting sparsity of the orientation distribution. Recent methods have proposed a global denoising of the diffusion data using spatial information prior to reconstruction, while others promote spatial regularisation through an additional empirical prior on the diffusion image at each q-space point. Our approach reconciles voxelwise sparsity and spatial regularisation and defines a spatially structured FOD sparsity prior, where the structure originates from the spatial coherence of the fibre orientation between neighbour voxels. The method is shown, through both simulated and real data, to enable accurate FOD reconstruction from a much lower number of q-space samples than the state of the art, typically 15 samples, even for quite adverse noise conditions.

Full-Body MRI in Patients With an Implantable Cardioverter-Defibrillator: Primary Results of a Randomized Study.

BACKGROUND: Magnetic resonance imaging (MRI) of patients with conventional implantable cardioverter-defibrillators (ICD) is contraindicated. OBJECTIVES: This multicenter, randomized trial evaluated safety and efficacy of a novel ICD system specially designed for full-body MRI without restrictions on heart rate or pacing dependency. The primary safety objective was >90% freedom from MRI-related events composite endpoint within 30 days post-MRI. The primary efficacy endpoints were ventricular pacing capture threshold and ventricular sensing amplitude. METHODS: Subjects received either a single- or dual-chamber ICD. In a 2:1 randomization, subjects either underwent MRI at 1.5-T of the chest, cervical, and head regions to maximize radiofrequency exposure up to 2 W/kg specific absorption rate and gradient field exposure to 200 T/m/s per axis (MRI group, n = 175), or they underwent a 1-h waiting period without MRI (control group, n = 88). A subset of MRI patients underwent ventricular fibrillation induction testing post-MRI to characterize defibrillation function. RESULTS: In 42 centers, 275 patients were enrolled (76% male, age 60.4 ± 13.8 years). The safety endpoint was met with 100% freedom from the composite endpoint (p < 0.0001). Both efficacy endpoints were met with minimal differences in the proportion of MRI and control patients who demonstrated a ≤0.5 V increase in ventricular pacing capture threshold (100% MRI vs. 98.8% control, noninferiority p < 0.0001) or a ≤50% decrease in R-wave amplitude (99.3% MRI vs. 98.8% control, noninferiority p = 0.0001). A total of 34 ventricular tachyarrhythmia/ventricular fibrillation episodes (20 induced; 14 spontaneous) occurred in 24 subjects post-MRI, with no observed effect on sensing, detection, or treatment. CONCLUSIONS: This is the first randomized clinical study of an ICD system designed for full-body MRI at 1.5-T. These data support that the system is safe and the MRI scan does not adversely affect electrical performance or efficacy. (Confirmatory Clinical Trial of the Evera MRI System for Conditionally-Safe MRI Access; NCT02117414).

Coronary vasomotor responses to isometric handgrip exercise are primarily mediated by nitric oxide: a noninvasive MRI test of coronary endothelial function.

Endothelial cell release of nitric oxide (NO) is a defining characteristic of nondiseased arteries, and abnormal endothelial NO release is both a marker of early atherosclerosis and a predictor of its progression and future events. Healthy coronaries respond to endothelial-dependent stressors with vasodilatation and increased coronary blood flow (CBF), but those with endothelial dysfunction respond with paradoxical vasoconstriction and reduced CBF. Recently, coronary MRI and isometric handgrip exercise (IHE) were reported to noninvasively quantify coronary endothelial function (CEF). However, it is not known whether the coronary response to IHE is actually mediated by NO and/or whether it is reproducible over weeks. To determine the contribution of NO, we studied the coronary response to IHE before and during infusion of N(G)-monomethyl-l-arginine (l-NMMA, 0.3 mg·kg(-1)·min(-1)), a NO-synthase inhibitor, in healthy volunteers. For reproducibility, we performed two MRI-IHE studies ∼8 wk apart in healthy subjects and patients with coronary artery disease (CAD). Changes from rest to IHE in coronary cross-sectional area (%CSA) and diastolic CBF (%CBF) were quantified. l-NMMA completely blocked normal coronary vasodilation during IHE [%CSA, 12.9 ± 2.5 (mean ± SE, placebo) vs. -0.3 ± 1.6% (l-NMMA); P < 0.001] and significantly blunted the increase in flow [%CBF, 47.7 ± 6.4 (placebo) vs. 10.6 ± 4.6% (l-NMMA); P < 0.001]. MRI-IHE measures obtained weeks apart strongly correlated for CSA (P < 0.0001) and CBF (P < 0.01). In conclusion, the normal human coronary vasoactive response to IHE is primarily mediated by NO. This noninvasive, reproducible MRI-IHE exam of NO-mediated CEF promises to be useful for studying CAD pathogenesis in low-risk populations and for evaluating translational strategies designed to alter CAD in patients.

A multi-contrast MRI study of microstructural brain damage in patients with mild cognitive impairment.

OBJECTIVES: The aim of this study was to investigate pathological mechanisms underlying brain tissue alterations in mild cognitive impairment (MCI) using multi-contrast 3 T magnetic resonance imaging (MRI). METHODS: Forty-two MCI patients and 77 healthy controls (HC) underwent T1/T2* relaxometry as well as Magnetization Transfer (MT) MRI. Between-groups comparisons in MRI metrics were performed using permutation-based tests. Using MRI data, a generalized linear model (GLM) was computed to predict clinical performance and a support-vector machine (SVM) classification was used to classify MCI and HC subjects. RESULTS: Multi-parametric MRI data showed microstructural brain alterations in MCI patients vs HC that might be interpreted as: (i) a broad loss of myelin/cellular proteins and tissue microstructure in the hippocampus (p ≤ 0.01) and global white matter (p < 0.05); and (ii) iron accumulation in the pallidus nucleus (p ≤ 0.05). MRI metrics accurately predicted memory and executive performances in patients (p ≤ 0.005). SVM classification reached an accuracy of 75% to separate MCI and HC, and performed best using both volumes and T1/T2*/MT metrics. CONCLUSION: Multi-contrast MRI appears to be a promising approach to infer pathophysiological mechanisms leading to brain tissue alterations in MCI. Likewise, parametric MRI data provide powerful correlates of cognitive deficits and improve automatic disease classification based on morphometric features.

Virtual milgram : empathic concern or personal distress? Evidence from functional MRI and dispositional measures

One motive for behaving as the agent of another"s aggression appears to be anchored in as yet unelucidated mechanisms of obedience to authority. In a recent partial replication of Milgram"s obedience paradigm within an immersive virtual environment, participants administered pain to a female virtual human and observed her suffering. Whether the participants" response to the latter was more akin to other-oriented empathic concern for her well-being or to a self-oriented aversive state of personal distress in response to her distress is unclear. Using the stimuli from that study, this event-related fMRI-based study analysed brain activity during observation of the victim in pain versus not in pain. This contrast revealed activation in pre-defi ned brain areas known to be involved in affective processing but not in those commonly associated with affect sharing (e.g., ACC and insula). We then examined whether different dimensions of dispositional empathy predict activity within the same pre-defi ned brain regions: While personal distress and fantasy (i.e., tendency to transpose oneself into fi ctional situations and characters) predicted brain activity, empathic concern and perspective taking predicted no change in neuronal response associated with pain observation. These exploratory fi ndings suggest that there is a distinct pattern of brain activity associated with observing the pain-related behaviour of the victim within the context of this social dilemma, that this observation evoked a self-oriented aversive state of personal distress, and that the objective"reality" of pain is of secondary importance for this response. These fi ndings provide a starting point for experimentally more rigorous investigation of obedience.

Advances in MRI-based computational neuroanatomy: from morphometry to in-vivo histology.

PURPOSE OF REVIEW: Current computational neuroanatomy based on MRI focuses on morphological measures of the brain. We present recent methodological developments in quantitative MRI (qMRI) that provide standardized measures of the brain, which go beyond morphology. We show how biophysical modelling of qMRI data can provide quantitative histological measures of brain tissue, leading to the emerging field of in-vivo histology using MRI (hMRI). RECENT FINDINGS: qMRI has greatly improved the sensitivity and specificity of computational neuroanatomy studies. qMRI metrics can also be used as direct indicators of the mechanisms driving observed morphological findings. For hMRI, biophysical models of the MRI signal are being developed to directly access histological information such as cortical myelination, axonal diameters or axonal g-ratio in white matter. Emerging results indicate promising prospects for the combined study of brain microstructure and function. SUMMARY: Non-invasive brain tissue characterization using qMRI or hMRI has significant implications for both research and clinics. Both approaches improve comparability across sites and time points, facilitating multicentre/longitudinal studies and standardized diagnostics. hMRI is expected to shed new light on the relationship between brain microstructure, function and behaviour, both in health and disease, and become an indispensable addition to computational neuroanatomy.

An efficient total variation algorithm for super-resolution in fetal brain MRI with adaptive regularization.

Although fetal anatomy can be adequately viewed in new multi-slice MR images, many critical limitations remain for quantitative data analysis. To this end, several research groups have recently developed advanced image processing methods, often denoted by super-resolution (SR) techniques, to reconstruct from a set of clinical low-resolution (LR) images, a high-resolution (HR) motion-free volume. It is usually modeled as an inverse problem where the regularization term plays a central role in the reconstruction quality. Literature has been quite attracted by Total Variation energies because of their ability in edge preserving but only standard explicit steepest gradient techniques have been applied for optimization. In a preliminary work, it has been shown that novel fast convex optimization techniques could be successfully applied to design an efficient Total Variation optimization algorithm for the super-resolution problem. In this work, two major contributions are presented. Firstly, we will briefly review the Bayesian and Variational dual formulations of current state-of-the-art methods dedicated to fetal MRI reconstruction. Secondly, we present an extensive quantitative evaluation of our SR algorithm previously introduced on both simulated fetal and real clinical data (with both normal and pathological subjects). Specifically, we study the robustness of regularization terms in front of residual registration errors and we also present a novel strategy for automatically select the weight of the regularization as regards the data fidelity term. Our results show that our TV implementation is highly robust in front of motion artifacts and that it offers the best trade-off between speed and accuracy for fetal MRI recovery as in comparison with state-of-the art methods.