Spatiotemporal alignment of in utero BOLD-MRI series

Purpose: To present a method for spatiotemporal alignment of in-utero magnetic resonance imaging (MRI) time series acquired during maternal hyperoxia for enabling improved quantitative tracking of blood oxygen level-dependent (BOLD) signal changes that characterize oxygen transport through the placenta to fetal organs. Materials and Methods: The proposed pipeline for spatiotemporal alignment of images acquired with a single-shot gradient echo echo-planar imaging includes 1) signal nonuniformity correction, 2) intravolume motion correction based on nonrigid registration, 3) correction of motion and nonrigid deformations across volumes, and 4) detection of the outlier volumes to be discarded from subsequent analysis. BOLD MRI time series collected from 10 pregnant women during 3T scans were analyzed using this pipeline. To assess pipeline performance, signal fluctuations between consecutive timepoints were examined. In addition, volume overlap and distance between manual region of interest (ROI) delineations in a subset of frames and the delineations obtained through propagation of the ROIs from the reference frame were used to quantify alignment accuracy. A previously demonstrated rigid registration approach was used for comparison. Results: The proposed pipeline improved anatomical alignment of placenta and fetal organs over the state-of-the-art rigid motion correction methods. In particular, unexpected temporal signal fluctuations during the first normoxia period were significantly decreased (P < 0.01) and volume overlap and distance between region boundaries measures were significantly improved (P < 0.01). Conclusion: The proposed approach to align MRI time series enables more accurate quantitative studies of placental function by improving spatiotemporal alignment across placenta and fetal organs.National Institutes of Health (NIH) . Grant Numbers: U01 HD087211 , R01 EB017337 Consejeria de Educacion, Juventud y Deporte de la Comunidad de Madrid (Spain) through the Madrid-MIT M+Vision Consortium

Motion robust acquisition and reconstruction of quantitative T2* maps in the developing brain

The goal of the research presented in this thesis was to develop methods for quantitative T2* mapping of the developing brain. Brain maturation in the early period of life involves complex structural and physiological changes caused by synaptogenesis, myelination and growth of cells. Molecular structures and biological processes give rise to varying levels of T2* relaxation time, which is an inherent contrast mechanism in magnetic resonance imaging. The knowledge of T2* relaxation times in the brain can thus help with evaluation of pathology by establishing its normative values in the key areas of the brain. T2* relaxation values are a valuable biomarker for myelin microstructure and iron concentration, as well as an important guide towards achievement of optimal fMRI contrast. However, fetal MR imaging is a significant step up from neonatal or adult MR imaging due to the complexity of the acquisition and reconstruction techniques that are required to provide high quality artifact-free images in the presence of maternal respiration and unpredictable fetal motion. The first contribution of this thesis, described in Chapter 4, presents a novel acquisition method for measurement of fetal brain T2* values. At the time of publication, this was the first study of fetal brain T2* values. Single shot multi-echo gradient echo EPI was proposed as a rapid method for measuring fetal T2* values by effectively freezing intra-slice motion. The study concluded that fetal T2* values are higher than those previously reported for pre-term neonates and decline with a consistent trend across gestational age. The data also suggested that longer than usual echo times or direct T2* measurement should be considered when performing fetal fMRI in order to reach optimal BOLD sensitivity. For the second contribution, described in Chapter 5, measurements were extended to a higher field strength of 3T and reported, for the first time, both for fetal and neonatal subjects at this field strength. The technical contribution of this work is a fully automatic segmentation framework that propagates brain tissue labels onto the acquired T2* maps without the need for manual intervention. The third contribution, described in Chapter 6, proposed a new method for performing 3D fetal brain reconstruction where the available data is sparse and is therefore limited in the use of current state of the art techniques for 3D brain reconstruction in the presence of motion. To enable a high resolution reconstruction, a generative adversarial network was trained to perform image to image translation between T2 weighted and T2* weighted data. Translated images could then be served as a prior for slice alignment and super resolution reconstruction of 3D brain image.Open Acces

Novel Image Processing Methods for Improved Fetal Brain MRI

Fetal magnetic resonance imaging (MRI) has been increasingly used as a powerful complement imaging modality to ultrasound imaging (US) for the clinical evaluation of prenatal abnormalities. Specifically, clinical application of fetal MRI has been significantly improved in the nineties by hardware and software advances with the development of ultrafast multi-slice T2-weighted (T2w) acquisition sequences able to freeze the unpredictable fetal motion and provide excellent soft-tissue contrast. Fetal motion is indeed the major challenge in fetal MRI and slice acquisition time should be kept as short as possible. As a result, typical fetal MRI examination involves the acquisition of a set of orthogonally planned scans of thick two-dimensional slices, largely free of intra-slice motion artifacts. The poor resolution in the slice-select dimension as well as possible motion occurring between slices limits further quantitative data analysis, which is the key for a better understanding of the developing brain but also the key for the determination of operator-independent biomarkers that might significantly facilitate fetal diagnosis and prognosis. To this end, several research groups have developed in the past ten years advanced image processing methods, often denoted by motion-robust super-resolution (SR) techniques, to reconstruct from a set of clinical low-resolution (LR) scans, a high-resolution (HR) motion-free volume. SR problem is usually modeled as a linear inverse problem describing the imaging degradation due to acquisition and fetal motion. Typically, such approaches consist in iterating between slice motion estimation that estimates the motion parameters and SR that recovers the HR image given the estimated degradation model. This thesis focuses on the development of novel advanced image processing methods, which have enabled the design of a completely automated reconstruction pipeline for fetal MRI. The proposed techniques help in improving state-of-the-art fetal MRI reconstruction in terms of efficiency, robustness and minimized user-interactions, with the ultimate goal of being translated to the clinical environment. The first part focuses on the development of a more efficient Total Variation (TV)-regularized optimization algorithm for the SR problem. The algorithm uses recent advances in convex optimization with a novel adaptive regularization strategy to offer simultaneously fast, accurate and robust solutions to the fetal image recovery problem. Extensive validations on both simulated fetal and real clinical data show the proposed algorithm 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. The second part focuses on the development of a novel automatic brain localization and extraction approach based on template-to-slice block matching and deformable slice-totemplate registration. Asmost fetal brain MRI reconstruction algorithms rely only on brain tissue-relevant voxels of low-resolution (LR) images to enhance the quality of inter-slice motion correction and image reconstruction, the fetal brain needs to be localized and extracted as a first step. These tasks generally necessitate user interaction, manually or semi-automatically done. Our methods have enabled the design of completely automated reconstruction pipeline that involves intensity normalization, inter-slice motion estimation, and super-resolution. Quantitative evaluation on clinical MRI scans shows that our approach produces brain masks that are very close to manually drawn brain masks, and ratings performed by two expert observers show that the proposed pipeline achieves similar reconstruction quality to reference reconstruction based on manual slice-by-slice brain extraction without any further effort. The third part investigates the possibility of automatic cortical folding quantification, one of the best biomarkers of brain maturation, by combining our automatic reconstruction pipeline with a state-of-the-art fetal brain tissue segmentation method and existing automated tools provided for adult brain’s cortical folding quantification. Results indicate that our reconstruction pipeline can provide HR MR images with sufficient quality that enable the use of surface tessellation and active surface algorithms similar to those developed for adults to extract meaningful information about fetal brain maturation. Finally, the last part presents new methodological improvements of the reconstruction pipeline aiming at improving the quality of the image for quantitative data analysis, whose accuracy is highly dependent on the quality and resolution of the reconstructed image. In particular, it presents a more consistent and global magnetic bias field correction method which takes advantage of the super-resolution framework to provide a final reconstructed image quasi free of the smooth bias field. Then, it presents a new TV SR algorithm that uses the Huber norm in the data fidelity term to be more robust to non-Gaussian outliers. It also presents the design of a novel joint reconstruction-segmentation framework and the development of a novel TV SR algorithm driven by segmentation to produce images with enhanced edge information that could ultimately improve their segmentation. Finally, it preliminary investigates the capability of increasing the resolution in the in-plane dimensions using SR to ultimately reduce the partial volume effect

Volumetric MRI Reconstruction from 2D Slices in the Presence of Motion

Despite recent advances in acquisition techniques and reconstruction algorithms, magnetic resonance imaging (MRI) remains challenging in the presence of motion. To mitigate this, ultra-fast two-dimensional (2D) MRI sequences are often used in clinical practice to acquire thick, low-resolution (LR) 2D slices to reduce in-plane motion. The resulting stacks of thick 2D slices typically provide high-quality visualizations when viewed in the in-plane direction. However, the low spatial resolution in the through-plane direction in combination with motion commonly occurring between individual slice acquisitions gives rise to stacks with overall limited geometric integrity. In further consequence, an accurate and reliable diagnosis may be compromised when using such motion-corrupted, thick-slice MRI data. This thesis presents methods to volumetrically reconstruct geometrically consistent, high-resolution (HR) three-dimensional (3D) images from motion-corrupted, possibly sparse, low-resolution 2D MR slices. It focuses on volumetric reconstructions techniques using inverse problem formulations applicable to a broad field of clinical applications in which associated motion patterns are inherently different, but the use of thick-slice MR data is current clinical practice. In particular, volumetric reconstruction frameworks are developed based on slice-to-volume registration with inter-slice transformation regularization and robust, complete-outlier rejection for the reconstruction step that can either avoid or efficiently deal with potential slice-misregistrations. Additionally, this thesis describes efficient Forward-Backward Splitting schemes for image registration for any combination of differentiable (not necessarily convex) similarity measure and convex (not necessarily smooth) regularization with a tractable proximal operator. Experiments are performed on fetal and upper abdominal MRI, and on historical, printed brain MR films associated with a uniquely long-term study dating back to the 1980s. The results demonstrate the broad applicability of the presented frameworks to achieve robust reconstructions with the potential to improve disease diagnosis and patient management in clinical practice

Congenital Zika virus infection as a silent pathology with loss of neurogenic output in the fetal brain

Zika virus (ZIKV) is a flavivirus with teratogenic effects on fetal brain, but the spectrum of ZIKV-induced brain injury is unknown, particularly when ultrasound imaging is normal. In a pregnant pigtail macaque (Macaca nemestrina) model of ZIKV infection, we demonstrate that ZIKV-induced injury to fetal brain is substantial, even in the absence of microcephaly, and may be challenging to detect in a clinical setting. A common and subtle injury pattern was identified, including (i) periventricular T2-hyperintense foci and loss of fetal noncortical brain volume, (ii) injury to the ependymal epithelium with underlying gliosis and (iii) loss of late fetal neuronal progenitor cells in the subventricular zone (temporal cortex) and subgranular zone (dentate gyrus, hippocampus) with dysmorphic granule neuron patterning. Attenuation of fetal neurogenic output demonstrates potentially considerable teratogenic effects of congenital ZIKV infection even without microcephaly. Our findings suggest that all children exposed to ZIKV in utero should receive long-term monitoring for neurocognitive deficits, regardless of head size at birth

Computerized Analysis of Magnetic Resonance Images to Study Cerebral Anatomy in Developing Neonates

The study of cerebral anatomy in developing neonates is of great importance for the understanding of brain development during the early period of life. This dissertation therefore focuses on three challenges in the modelling of cerebral anatomy in neonates during brain development. The methods that have been developed all use Magnetic Resonance Images (MRI) as source data. To facilitate study of vascular development in the neonatal period, a set of image analysis algorithms are developed to automatically extract and model cerebral vessel trees. The whole process consists of cerebral vessel tracking from automatically placed seed points, vessel tree generation, and vasculature registration and matching. These algorithms have been tested on clinical Time-of- Flight (TOF) MR angiographic datasets. To facilitate study of the neonatal cortex a complete cerebral cortex segmentation and reconstruction pipeline has been developed. Segmentation of the neonatal cortex is not effectively done by existing algorithms designed for the adult brain because the contrast between grey and white matter is reversed. This causes pixels containing tissue mixtures to be incorrectly labelled by conventional methods. The neonatal cortical segmentation method that has been developed is based on a novel expectation-maximization (EM) method with explicit correction for mislabelled partial volume voxels. Based on the resulting cortical segmentation, an implicit surface evolution technique is adopted for the reconstruction of the cortex in neonates. The performance of the method is investigated by performing a detailed landmark study. To facilitate study of cortical development, a cortical surface registration algorithm for aligning the cortical surface is developed. The method first inflates extracted cortical surfaces and then performs a non-rigid surface registration using free-form deformations (FFDs) to remove residual alignment. Validation experiments using data labelled by an expert observer demonstrate that the method can capture local changes and follow the growth of specific sulcus

Transmission-based attenuation correction for time-of-flight positron emission tomography

Positronemissietomografie (PET) is een beeldvormingstechniek binnen de nucleaire geneeskunde waarbij met behulp van een radioactieve speurstof fysiologische processen in het lichaam in beeld gebracht worden. De techniek speelt een belangrijke rol in de diagnose van verschillende aandoeningen. Het verkrijgen van kwantitatieve PET beelden wordt echter bemoeilijkt door een aantal fysische effecten. Eén van de voornaamste effecten is de attenuatie van de fotonen uitgezonden door de speurstof. Om hiervoor te corrigeren, dient de verdeling van attenuatiecoëfficiënten binnen het beeldvolume gekend te zijn. PET beeldvorming is gedurende de laatste tien jaar geëvolueerd tot multimodale beeldvorming, waarbij functionele PET gecombineerd wordt met magnetische resonantiebeeldvorming (MRI). Het corrigeren voor attenuatie in een PET/MRI-studie is echter niet zo eenvoudig aangezien er geen rechtstreeks verband bestaat tussen de MRI-signalen en de attenuatiecoëfficiënten van weefsels. In dit onderzoek werd een nieuwe MR-compatibele methode ontwikkeld om de verdeling van de attenuatiecoëfficiënten van weefsels in een 'Time-Of-Flight' (TOF) PET-opname te bepalen. Hiervoor wordt gebruik gemaakt van een transmissiebron die binnen het beeldvolume wordt gebracht. Tevens laat de TOF-informatie toe de transmissie- en emissiedata simultaan op te meten. De methode werd getest met een simulatie-studie, experimentele studies en humane beeldvorming

Registration and Modeling from Spaced and Misaligned Image Volumes

We present an integrated registration, segmentation, and shape interpolation framework to model objects from 3D and 4D volumes made up of spaced and misaligned slices having arbitrary relative positions. The framework was validated on artificial data and tested on real MRI and CT scans. The complete framework performed significantly better than the sequential approach of registration followed by segmentation and shape interpo- lation

Improving Quantification in Lung PET/CT for the Evaluation of Disease Progression and Treatment Effectiveness

Positron Emission Tomography (PET) allows imaging of functional processes in vivo by measuring the distribution of an administered radiotracer. Whilst one of its main uses is directed towards lung cancer, there is an increased interest in diffuse lung diseases, for which the incidences rise every year, mainly due to environmental reasons and population ageing. However, PET acquisitions in the lung are particularly challenging due to several effects, including the inevitable cardiac and respiratory motion and the loss of spatial resolution due to low density, causing increased positron range. This thesis will focus on Idiopathic Pulmonary Fibrosis (IPF), a disease whose aetiology is poorly understood while patient survival is limited to a few years only. Contrary to lung tumours, this diffuse lung disease modifies the lung architecture more globally. The changes result in small structures with varying densities. Previous work has developed data analysis techniques addressing some of the challenges of imaging patients with IPF. However, robust reconstruction techniques are still necessary to obtain quantitative measures for such data, where it should be beneficial to exploit recent advances in PET scanner hardware such as Time of Flight (TOF) and respiratory motion monitoring. Firstly, positron range in the lung will be discussed, evaluating its effect in density-varying media, such as fibrotic lung. Secondly, the general effect of using incorrect attenuation data in lung PET reconstructions will be assessed. The study will compare TOF and non-TOF reconstructions and quantify the local and global artefacts created by data inconsistencies and respiratory motion. Then, motion compensation will be addressed by proposing a method which takes into account the changes of density and activity in the lungs during the respiration, via the estimation of the volume changes using the deformation fields. The method is evaluated on late time frame PET acquisitions using ¹⁸F-FDG where the radiotracer distribution has stabilised. It is then used as the basis for a method for motion compensation of the early time frames (starting with the administration of the radiotracer), leading to a technique that could be used for motion compensation of kinetic measures. Preliminary results are provided for kinetic parameters extracted from short dynamic data using ¹⁸F-FDG

Hybrid Kernelised Expectation Maximisation Reconstruction Algorithms for Quantitative Positron Emission Tomography

Positron emission tomography (PET) imaging is commonly used in clinical practice to diagnose different diseases. However, the limited spatial resolution sometimes prevents the desired diagnostic accuracy. This work examines some of the issues related to PET image reconstruction in the context of PET-magnetic resonance (MR) imaging, and proposes a novel PET iterative reconstruction algorithm, hybrid kernelised expectation maximisation (HKEM), to overcome these issues by exploiting synergistic information from PET and MR images. When the number of detected events is low, the reconstructed images are often biased and noisy. Anatomically-guided PET image reconstruction techniques have been demonstrated to reduce partial volume effect (PVE), noise, and improve quantification, but, they have also been shown to rely on the accurate registration between the anatomical image and the PET image, otherwise they may suppress important PET information that may lead to false negative detection of disease. The aim of the HKEM algorithm is to maintain the benefits of the anatomically-guided methods and overcome their limitations by incorporating synergistic information iteratively. The findings obtained using simulated and real datasets, by performing region of interest (ROI) analysis and voxel-wise analysis are as follows: first, anatomically-guided techniques provide reduced PVE and higher contrast compared to standard techniques, and HKEM provides even higher contrast in almost all the cases; second, the absolute bias and the noise affecting low-count datasets is reduced; third, HKEM reduces PET unique features suppression due to PET-MR spatial inconsistency. This thesis, therefore argues that using synergistic information, via the kernel method, increases the accuracy and precision of the PET clinical diagnostic examination. The promising quantitative features of the HKEM method give the opportunity to explore many possible clinical applications, such as cancer and inflammation