In vivo T2 measurements of the fetal brain using single-shot fast spin echo sequences.

PURPOSE: We propose a quantitative framework for motion-corrected T2 fetal brain measurements in vivo and validate the single-shot fast spin echo (SS-FSE) sequence to perform these measurements. METHODS: Stacks of two-dimensional SS-FSE slices are acquired with different echo times (TE) and motion-corrected with slice-to-volume reconstruction (SVR). The quantitative T2 maps are obtained by a fit to a dictionary of simulated signals. The sequence is selected using simulated experiments on a numerical phantom and validated on a physical phantom scanned on a 1.5T system. In vivo quantitative T2 maps are obtained for five fetuses with gestational ages (GA) 21-35 weeks on the same 1.5T system. RESULTS: The simulated experiments suggested that a TE of 400 ms combined with the clinically utilized TEs of 80 and 180 ms were most suitable for T2 measurements in the fetal brain. The validation on the physical phantom confirmed that the SS-FSE T2 measurements match the gold standard multi-echo spin echo measurements. We measured average T2s of around 200 and 280 ms in the fetal brain grey and white matter, respectively. This was slightly higher than fetal T2* and the neonatal T2 obtained from previous studies. CONCLUSION: The motion-corrected SS-FSE acquisitions with varying TEs offer a promising practical framework for quantitative T2 measurements of the moving fetus.

Widespread, depth-dependent cortical microstructure alterations in pediatric focal epilepsy.

OBJECTIVE: Tissue abnormalities in focal epilepsy may extend beyond the presumed focus. The underlying pathophysiology of these broader changes is unclear, and it is not known whether they result from ongoing disease processes or treatment-related side effects, or whether they emerge earlier. Few studies have focused on the period of onset for most focal epilepsies, childhood. Fewer still have utilized quantitative magnetic resonance imaging (MRI), which may provide a more sensitive and interpretable measure of tissue microstructural change. Here, we aimed to determine common spatial modes of changes in cortical architecture in children with heterogeneous drug-resistant focal epilepsy and, secondarily, whether changes were related to disease severity. METHODS: To assess cortical microstructure, quantitative T1 and T2 relaxometry (qT1 and qT2) was measured in 43 children with drug-resistant focal epilepsy (age range = 4-18 years) and 46 typically developing children (age range = 2-18 years). We assessed depth-dependent qT1 and qT2 values across the neocortex, as well as their gradient of change across cortical depths. We also determined whether global changes seen in group analyses were driven by focal pathologies in individual patients. Finally, as a proof-of-concept, we trained a classifier using qT1 and qT2 gradient maps from patients with radiologically defined abnormalities (MRI positive) and healthy controls, and tested whether this could classify patients without reported radiological abnormalities (MRI negative). RESULTS: We uncovered depth-dependent qT1 and qT2 increases in widespread cortical areas in patients, likely representing microstructural alterations in myelin or gliosis. Changes did not correlate with disease severity measures, suggesting they may represent antecedent neurobiological alterations. Using a classifier trained with MRI-positive patients and controls, sensitivity was 71.4% at 89.4% specificity on held-out MRI-negative patients. SIGNIFICANCE: These findings suggest the presence of a potential imaging endophenotype of focal epilepsy, detectable irrespective of radiologically identified abnormalities.

Quantitative magnetization transfer imaging for non-contrast enhanced detection of myocardial fibrosis.

PURPOSE: To develop a novel gadolinium-free model-based quantitative magnetization transfer (qMT) technique to assess macromolecular changes associated with myocardial fibrosis. METHODS: The proposed sequence consists of a two-dimensional breath-held dual shot interleaved acquisition of five MT-weighted (MTw) spoiled gradient echo images, with variable MT flip angles (FAs) and off-resonance frequencies. A two-pool exchange model and dictionary matching were used to quantify the pool size ratio (PSR) and bound pool T2 relaxation ( T2B ). The signal model was developed and validated using 25 MTw images on a bovine serum albumin (BSA) phantom and in vivo human thigh muscle. A protocol with five MTw images was optimized for single breath-hold cardiac qMT imaging. The proposed sequence was tested in 10 healthy subjects and 5 patients with myocardial fibrosis and compared to late gadolinium enhancement (LGE). RESULTS: PSR values in the BSA phantom were within the confidence interval of previously reported values (concentration 10% BSA = 5.9 ± 0.1%, 15% BSA = 9.4 ± 0.2%). PSR and T2B in thigh muscle were also in agreement with literature (PSR = 10.9 ± 0.3%, T2B = 6.4 ± 0.4 us). In 10 healthy subjects, global left ventricular PSR was 4.30 ± 0.65%. In patients, PSR was reduced in areas associated with LGE (remote: 4.68 ± 0.70% vs. fibrotic: 3.12 ± 0.78 %, n = 5, P < .002). CONCLUSION: In vivo model-based qMT mapping of the heart was performed for the first time, with promising results for non-contrast enhanced assessment of myocardial fibrosis.

Motion-corrected MRI with DISORDER: Distributed and incoherent sample orders for reconstruction deblurring using encoding redundancy.

PURPOSE: To enable rigid body motion-tolerant parallel volumetric magnetic resonance imaging by retrospective head motion correction on a variety of spatiotemporal scales and imaging sequences. THEORY AND METHODS: Tolerance against rigid body motion is based on distributed and incoherent sampling orders for boosting a joint retrospective motion estimation and reconstruction framework. Motion resilience stems from the encoding redundancy in the data, as generally provided by the coil array. Hence, it does not require external sensors, navigators or training data, so the methodology is readily applicable to sequences using 3D encodings. RESULTS: Simulations are performed showing full inter-shot corrections for usual levels of in vivo motion, large number of shots, standard levels of noise and moderate acceleration factors. Feasibility of inter- and intra-shot corrections is shown under controlled motion in vivo. Practical efficacy is illustrated by high-quality results in most corrupted of 208 volumes from a series of 26 clinical pediatric examinations collected using standard protocols. CONCLUSIONS: The proposed framework addresses the rigid motion problem in volumetric anatomical brain scans with sufficient encoding redundancy which has enabled reliable pediatric examinations without sedation.

Construction of a neonatal cortical surface atlas using Multimodal Surface Matching in the Developing Human Connectome Project.

We propose a method for constructing a spatio-temporal cortical surface atlas of neonatal brains aged between 36 and 44 weeks of post-menstrual age (PMA) at the time of scan. The data were acquired as part of the Developing Human Connectome Project (dHCP), and the constructed surface atlases are publicly available. The method is based on a spherical registration approach: Multimodal Surface Matching (MSM), using cortical folding for driving the alignment. Templates have been generated for the anatomical cortical surface and for the cortical feature maps: sulcal depth, curvature, thickness, T1w/T2w myelin maps and cortical regions. To achieve this, cortical surfaces from 270 infants were first projected onto the sphere. Templates were then generated in two stages: first, a reference space was initialised via affine alignment to a group average adult template. Following this, templates were iteratively refined through repeated alignment of individuals to the template space until the variability of the average feature sets converged. Finally, bias towards the adult reference was removed by applying the inverse of the average affine transformations on the template and de-drifting the template. We used temporal adaptive kernel regression to produce age-dependant atlases for 9 weeks (36-44 weeks PMA). The generated templates capture expected patterns of cortical development including an increase in gyrification as well as an increase in thickness and T1w/T2w myelination with increasing age.

The developing human connectome project: A minimal processing pipeline for neonatal cortical surface reconstruction.

The Developing Human Connectome Project (dHCP) seeks to create the first 4-dimensional connectome of early life. Understanding this connectome in detail may provide insights into normal as well as abnormal patterns of brain development. Following established best practices adopted by the WU-MINN Human Connectome Project (HCP), and pioneered by FreeSurfer, the project utilises cortical surface-based processing pipelines. In this paper, we propose a fully automated processing pipeline for the structural Magnetic Resonance Imaging (MRI) of the developing neonatal brain. This proposed pipeline consists of a refined framework for cortical and sub-cortical volume segmentation, cortical surface extraction, and cortical surface inflation, which has been specifically designed to address considerable differences between adult and neonatal brains, as imaged using MRI. Using the proposed pipeline our results demonstrate that images collected from 465 subjects ranging from 28 to 45 weeks post-menstrual age (PMA) can be processed fully automatically; generating cortical surface models that are topologically correct, and correspond well with manual evaluations of tissue boundaries in 85% of cases. Results improve on state-of-the-art neonatal tissue segmentation models and significant errors were found in only 2% of cases, where these corresponded to subjects with high motion. Downstream, these surfaces will enhance comparisons of functional and diffusion MRI datasets, supporting the modelling of emerging patterns of brain connectivity.

Joint system relaxometry (JSR) and Crámer-Rao lower bound optimization of sequence parameters: A framework for enhanced precision of DESPOT T1 and T2 estimation.

PURPOSE: This study aims to increase the precision of single-compartment DESPOT relaxometry by two means: (i) a joint system relaxometry (JSR) approach that estimates parameters in a single step using all available data; and (ii) optimizing acquisition parameters by deploying a robust design tool based on the Crámer-Rao lower bound (CRLB). METHODS: Following the development of the analysis and design capabilities, phantom and four in vivo subject experiments were performed to compare directly the precision achieved with DESPOT and JSR estimation using published protocols and protocols designed using a proposed CRLB framework. RESULTS: Experimental data demonstrate JSR's ability to decrease relaxometry estimation variance. Phantom results show 72 to 77% improvement using the same data as conventional DESPOT. This is further improved to 81 to 87% using optimal parameters. Both experiments show systematic bias depending on the acquisition parameters used, which are shown to be highly reproducible and to vary with different magnetization transfer conditions. CONCLUSIONS: Compared with DESPOT, JSR produces reproducible relaxation maps with improved precision. Further improvement was achieved using CRLB as a protocol design tool. With this combined approach, it is possible to achieve submillimeter maps of ρ,T1,T2, and B0 in an 11-min examination, making the approach appealing for potential clinical use. Magn Reson Med 79:234-245, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Extended phase graph formalism for systems with magnetization transfer and exchange.

PURPOSE: An extended phase graph framework (EPG-X) for modeling systems with exchange or magnetization transfer (MT) is proposed. THEORY: EPG-X models coupled two-compartment systems by describing each compartment with separate phase graphs that exchange during evolution periods. There are two variants: EPG-X(BM) for systems governed by the Bloch-McConnell equations, and EPG-X(MT) for the pulsed MT formalism. For the MT case, the "bound" protons have no transverse components, so their phase graph consists of only longitudinal states. METHODS: The EPG-X model was validated against steady-state solutions and isochromat-based simulation of gradient-echo sequences. Three additional test cases were investigated: (i) MT effects in multislice turbo spin-echo; (ii) variable flip angle gradient-echo imaging of the type used for MR fingerprinting; and (iii) water exchange in multi-echo spin-echo T2 relaxometry. RESULTS: EPG-X was validated successfully against isochromat based transient simulations and known steady-state solutions. EPG-X(MT) simulations matched in-vivo measurements of signal attenuation in white matter in multislice turbo spin-echo images. Magnetic resonance fingerprinting-style experiments with a bovine serum albumin (MT) phantom showed that the data were not consistent with a single-pool model, but EPG-X(MT) could be used to fit the data well. The EPG-X(BM) simulations of multi-echo spin-echo T2 relaxometry suggest that exchange could lead to an underestimation of the myelin-water fraction. CONCLUSIONS: The EPG-X framework can be used for modeling both steady-state and transient signal response of systems exhibiting exchange or MT. This may be particularly beneficial for relaxometry approaches that rely on characterizing transient rather than steady-state sequences. Magn Reson Med 80:767-779, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

An efficient sequence for fetal brain imaging at 3T with enhanced T1 contrast and motion robustness.

PURPOSE: Ultrafast single-shot T2 -weighted images are common practice in fetal MR exams. However, there is limited experience with fetal T1 -weighted acquisitions. This study aims at establishing a robust framework that allows fetal T1 -weighted scans to be routinely acquired in utero at 3T. METHODS: A 2D gradient echo sequence with an adiabatic inversion was optimized to be robust to fetal motion and maternal breathing optimizing grey/white matter contrast at the same time. This was combined with slice to volume registration and super resolution methods to produce volumetric reconstructions. The sequence was tested on 22 fetuses. RESULTS: Optimized grey/white matter contrast and robustness to fetal motion and maternal breathing were achieved. Signal from cerebrospinal fluid (CSF) and amniotic fluid was nulled and 0.75 mm isotropic anatomical reconstructions of the fetal brain were obtained using slice-to-volume registration and super resolution techniques. Total acquisition time for a single stack was 56 s, all acquired during free breathing. Enhanced sensitivity to normal anatomy and pathology with respect to established methods is demonstrated. A direct comparison with a 3D spoiled gradient echo sequence and a controlled motion experiment run on an adult volunteer are also shown. CONCLUSION: This paper describes a robust framework to perform T1 -weighted acquisitions and reconstructions of the fetal brain in utero. Magn Reson Med 80:137-146, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Efficiency analysis for quantitative MRI of T1 and T2 relaxometry methods.

This study presents a comparison of quantitative MRI methods based on an efficiency metric that quantifies their intrinsic ability to extract information about tissue parameters. Under a regime of unbiased parameter estimates, an intrinsic efficiency metricηwas derived for fully-sampled experiments which can be used to both optimize and compare sequences. Here we optimize and compare several steady-state and transient gradient-echo based qMRI methods, such as magnetic resonance fingerprinting (MRF), for jointT1andT2mapping. The impact of undersampling was also evaluated, assuming incoherent aliasing that is treated as noise by parameter estimation.In vivovalidation of the efficiency metric was also performed. Transient methods such as MRF can be up to 3.5 times more efficient than steady-state methods, when spatial undersampling is ignored. If incoherent aliasing is treated as noise during least-squares parameter estimation, the efficiency is reduced in proportion to the SNR of the data, with reduction factors of 5 often seen for practical SNR levels.In vivovalidation showed a very good agreement between the theoretical and experimentally predicted efficiency. This work presents and validates an efficiency metric to optimize and compare the performance of qMRI methods. Transient methods were found to be intrinsically more efficient than steady-state methods, however the effect of spatial undersampling can significantly erode this advantage.

Neuroimaging findings in newborns with congenital heart disease prior to surgery: an observational study.

OBJECTIVES: Neurodevelopmental impairment has become the most important comorbidity in infants with congenital heart disease (CHD). We aimed to (1) investigate the burden of brain lesions in infants with CHD prior to surgery and (2) explore clinical factors associated with injury. STUDY DESIGN: Prospective observational study. SETTING: Single centre UK tertiary neonatal intensive care unit. PATIENTS: 70 newborn infants with critical or serious CHD underwent brain MRI prior to surgery. MAIN OUTCOME MEASURES: Prevalence of cerebral injury including arterial ischaemic strokes (AIS), white matter injury (WMI) and intracranial haemorrhage. RESULTS: Brain lesions were observed in 39% of subjects (95% CI 28% to 50%). WMI was identified in 33% (95% CI 23% to 45%), subdural haemorrhage without mass effect in 33% (95% CI 23% to 45%), cerebellar haemorrhage in 9% (95% CI 4% to 18%) and AIS in 4% (95% CI 1.5% to 12%). WMI was distributed widely throughout the brain, particularly involving the frontal white matter, optic radiations and corona radiata. WMI exhibited restricted diffusion in 48% of cases. AIS was only observed in infants with transposition of the great arteries (TGA) who had previously undergone balloon atrial septostomy (BAS). AIS was identified in 23% (95% CI 8% to 50%) of infants with TGA who underwent BAS, compared with 0% (95% CI 0% to 20%) who did not. CONCLUSIONS: Cerebral injury in newborns with CHD prior to surgery is common.

Integrated and efficient diffusion-relaxometry using ZEBRA.

The emergence of multiparametric diffusion models combining diffusion and relaxometry measurements provides powerful new ways to explore tissue microstructure, with the potential to provide new insights into tissue structure and function. However, their ability to provide rich analyses and the potential for clinical translation critically depends on the availability of efficient, integrated, multi-dimensional acquisitions. We propose a fully integrated sequence simultaneously sampling the acquisition parameter spaces required for T1 and T2* relaxometry and diffusion MRI. Slice-level interleaved diffusion encoding, multiple spin/gradient echoes and slice-shuffling are combined for higher efficiency, sampling flexibility and enhanced internal consistency. In-vivo data was successfully acquired on healthy adult brains. Obtained parametric maps as well as clustering results demonstrate the potential of the technique to provide eloquent data with an acceleration of roughly 20 compared to conventionally used approaches. The proposed integrated acquisition, which we call ZEBRA, offers significant acceleration and flexibility compared to existing diffusion-relaxometry studies, and thus facilitates wider use of these techniques both for research-driven and clinical applications.

Impaired development of the cerebral cortex in infants with congenital heart disease is correlated to reduced cerebral oxygen delivery.

Neurodevelopmental impairment is the most common comorbidity associated with complex congenital heart disease (CHD), while the underlying biological mechanism remains unclear. We hypothesised that impaired cerebral oxygen delivery in infants with CHD is a cause of impaired cortical development, and predicted that cardiac lesions most associated with reduced cerebral oxygen delivery would demonstrate the greatest impairment of cortical development. We compared 30 newborns with complex CHD prior to surgery and 30 age-matched healthy controls using brain MRI. The cortex was assessed using high resolution, motion-corrected T2-weighted images in natural sleep, analysed using an automated pipeline. Cerebral oxygen delivery was calculated using phase contrast angiography and pre-ductal pulse oximetry, while regional cerebral oxygen saturation was estimated using near-infrared spectroscopy. We found that impaired cortical grey matter volume and gyrification index in newborns with complex CHD was linearly related to reduced cerebral oxygen delivery, and that cardiac lesions associated with the lowest cerebral oxygen delivery were associated with the greatest impairment of cortical development. These findings suggest that strategies to improve cerebral oxygen delivery may help reduce brain dysmaturation in newborns with CHD, and may be most relevant for children with CHD whose cardiac defects remain unrepaired for prolonged periods after birth.