Recommendations and guidelines from the ISMRM Diffusion Study Group for preclinical diffusion MRI: Part 1 -- In vivo small-animal imaging

The value of in vivo preclinical diffusion MRI (dMRI) is substantial. Small-animal dMRI has been used for methodological development and validation, characterizing the biological basis of diffusion phenomena, and comparative anatomy. Many of the influential works in this field were first performed in small animals or ex vivo samples. The steps from animal setup and monitoring, to acquisition, analysis, and interpretation are complex, with many decisions that may ultimately affect what questions can be answered using the data. This work aims to serve as a reference, presenting selected recommendations and guidelines from the diffusion community, on best practices for preclinical dMRI of in vivo animals. In each section, we also highlight areas for which no guidelines exist (and why), and where future work should focus. We first describe the value that small animal imaging adds to the field of dMRI, followed by general considerations and foundational knowledge that must be considered when designing experiments. We briefly describe differences in animal species and disease models and discuss how they are appropriate for different studies. We then give guidelines for in vivo acquisition protocols, including decisions on hardware, animal preparation, imaging sequences and data processing, including pre-processing, model-fitting, and tractography. Finally, we provide an online resource which lists publicly available preclinical dMRI datasets and software packages, to promote responsible and reproducible research. An overarching goal herein is to enhance the rigor and reproducibility of small animal dMRI acquisitions and analyses, and thereby advance biomedical knowledge.Comment: 69 pages, 6 figures, 1 tabl

Normative spatiotemporal fetal brain maturation with satisfactory development at 2 years

Maturation of the human fetal brain should follow precisely scheduled structural growth and folding of the cerebral cortex for optimal postnatal function1 . We present a normative digital atlas of fetal brain maturation based on a prospective international cohort of healthy pregnant women2 , selected using World Health Organization recommendations for growth standards3 . Their fetuses were accurately dated in the first trimester, with satisfactory growth and neurodevelopment from early pregnancy to 2 years of age4,5 . The atlas was produced using 1,059 optimal quality, three dimensional ultrasound brain volumes from 899 of the fetuses and an automated analysis pipeline6–8 . The atlas corresponds structurally to published magnetic resonance images9 , but with finer anatomical details in deep grey matter. The between study site variability represented less than 8.0% of the total variance of all brain measures, supporting pooling data from the eight study sites to produce patterns of normative maturation. We have thereby generated an average representation of each cerebral hemisphere between 14 and 31 weeks’ gestation with quantification of intracranial volume variability and growth patterns. Emergent asymmetries were detectable from as early as 14 weeks, with peak asymmetries in regions associated with language development and functional lateralization between 20 and 26 weeks’ gestation. These patterns were validated in 1,487 three-dimensional brain volumes from 1,295 different fetuses in the same cohort. We provide a unique spatiotemporal benchmark of fetal brain maturation from a large cohort with normative postnatal growth and neurodevelopment

Biomechanical models and mechanisms of cellular morphogenesis and cerebral cortical expansion and folding

Morphogenesis of the nervous system involves a highly complex spatio-temporal pattern of physical forces (mainly tension and pressure) acting on cells and tissues that are pliable but have an intricately organized cytoskeletal infrastructure. This review begins by covering basic principles of biomechanics and the core cytoskeletal toolkit used to regulate the shapes of cells and tissues during embryogenesis and neural development. It illustrates how the principle of \u27tensegrity\u27 provides a useful conceptual framework for understanding how cells dynamically respond to forces that are generated internally or applied externally. The latter part of the review builds on this foundation in considering the development of mammalian cerebral cortex. The main focus is on cortical expansion and folding - processes that take place over an extended period of prenatal and postnatal development. Cortical expansion and folding are likely to involve many complementary mechanisms, some related to regulating cell proliferation and migration and others related to specific types and patterns of mechanical tension and pressure. Three distinct multi-mechanism models are evaluated in relation to a set of 18 key experimental observations and findings. The Composite Tension Plus (CT+) model is introduced as an updated version of a previous multi-component Differential Expansion Sandwich Plus (DES+) model (Van Essen, 2020); the new CT+ model includes 10 distinct mechanisms and has the greatest explanatory power among published models to date. Much needs to be done in order to validate specific mechanistic components and to assess their relative importance in different species, and important directions for future research are suggested

Diffusion Tensor Imaging Biomarkers of Brain Development and Disease

<p>Understanding the structure of the brain has been a major goal of neuroscience research over the past century, driven in part by the understanding that brain structure closely follows function. Normative brain maps, or atlases, can be used to understand normal brain structure, and to identify structural differences resulting from disease. Recently, diffusion tensor magnetic resonance imaging has emerged as a powerful tool for brain atlasing; however, its utility is hindered by image resolution and signal limitations. These limitations can be overcome by imaging fixed ex-vivo specimens stained with MRI contrast agents, a technique known as diffusion tensor magnetic resonance histology (DT-MRH). DT-MRH represents a unique, quantitative tool for mapping the brain with unprecedented structural detail. This technique has engendered a new generation of 3D, digital brain atlases, capable of representing complex dynamic processes such as neurodevelopment. This dissertation explores the use of DT-MRH for quantitative brain atlasing in an animal model and initial work in the human brain. </p><p>Chapter 1 describes the advantages of the DT-MRH technique, and the motivations for generating a quantitative atlas of rat postnatal neurodevelopment. The second chapter covers optimization of the DT-MRH hardware and pulse sequence design for imaging the developing rat brain. Chapter 3 details the acquisition and curation of rat neurodevelopmental atlas data. Chapter 4 describes the creation and implementation of an ontology-based segmentation scheme for tracking changes in the developing brain. Chapters 5 and 6 pertain to analyses of volumetric changes and diffusion tensor parameter changes throughout rat postnatal neurodevelopment, respectively. Together, the first six chapters demonstrate many of the unique and scientifically valuable features of DT-MRH brain atlases in a popular animal model.</p><p>The final two chapters are concerned with translating the DT-MRH technique for use in human and non-human primate brain atlasing. Chapter 7 explores the validity of assumptions imposed by DT-MRH in the primate brain. Specifically, it analyzes computer models and experimental data to determine the extent to which intravoxel diffusion complexity exists in the rhesus macaque brain, a close model for the human brain. Finally, Chapter 8 presents conclusions and future directions for DT-MRH brain atlasing, and includes initial work in creating DT-MRH atlases of the human brain. In conclusion, this work demonstrates the utility of a DT-MRH brain atlasing with an atlas of rat postnatal neurodevelopment, and lays the foundation for creating a DT-MRH atlas of the human brain.</p>Dissertatio

Effect of perinatal adversity on structural connectivity of the developing brain

Globally, preterm birth (defined as birth at <37 weeks of gestation) affects around 11% of deliveries and it is closely associated with cerebral palsy, cognitive impairments and neuropsychiatric diseases in later life. Magnetic Resonance Imaging (MRI) has utility for measuring different properties of the brain during the lifespan. Specially, diffusion MRI has been used in the neonatal period to quantify the effect of preterm birth on white matter structure, which enables inference about brain development and injury. By combining information from both structural and diffusion MRI, is it possible to calculate structural connectivity of the brain. This involves calculating a model of the brain as a network to extract features of interest. The process starts by defining a series of nodes (anatomical regions) and edges (connections between two anatomical regions). Once the network is created, different types of analysis can be performed to find features of interest, thereby allowing group wise comparisons. The main frameworks/tools designed to construct the brain connectome have been developed and tested in the adult human brain. There are several differences between the adult and the neonatal brain: marked variation in head size and shape, maturational processes leading to changes in signal intensity profiles, relatively lower spatial resolution, and lower contrast between tissue classes in the T1 weighted image. All of these issues make the standard processes to construct the brain connectome very challenging to apply in the neonatal population. Several groups have studied the neonatal structural connectivity proposing several alternatives to overcome these limitations. The aim of this thesis was to optimise the different steps involved in connectome analysis for neonatal data. First, to provide accurate parcellation of the cortex a new atlas was created based on a control population of term infants; this was achieved by propagating the atlas from an adult atlas through intermediate childhood spatio-temporal atlases using image registration. After this the advanced anatomically-constrained tractography framework was adapted for the neonatal population, refined using software tools for skull-stripping, tissue segmentation and parcellation specially designed and tested for the neonatal brain. Finally, the method was used to test the effect of early nutrition, specifically breast milk exposure, on structural connectivity in preterm infants. We found that infants with higher exposure to breastmilk in the weeks after preterm birth had improved structural connectivity of developing networks and greater fractional anisotropy in major white matter fasciculi. These data also show that the benefits are dose dependent with higher exposure correlating with increased white matter connectivity. In conclusion, structural connectivity is a robust method to investigate the developing human brain. We propose an optimised framework for the neonatal brain, designed for our data and using tools developed for the neonatal brain, and apply it to test the effect of breastmilk exposure on preterm infants

Normative spatiotemporal fetal brain maturation with satisfactory development at 2 years.

Maturation of the human fetal brain should follow precisely scheduled structural growth and folding of the cerebral cortex for optimal postnatal function1. We present a normative digital atlas of fetal brain maturation based on a prospective international cohort of healthy pregnant women2, selected using World Health Organization recommendations for growth standards3. Their fetuses were accurately dated in the first trimester, with satisfactory growth and neurodevelopment from early pregnancy to 2 years of age4,5. The atlas was produced using 1,059 optimal quality, three-dimensional ultrasound brain volumes from 899 of the fetuses and an automated analysis pipeline6-8. The atlas corresponds structurally to published magnetic resonance images9, but with finer anatomical details in deep grey matter. The between-study site variability represented less than 8.0% of the total variance of all brain measures, supporting pooling data from the eight study sites to produce patterns of normative maturation. We have thereby generated an average representation of each cerebral hemisphere between 14 and 31 weeks' gestation with quantification of intracranial volume variability and growth patterns. Emergent asymmetries were detectable from as early as 14 weeks, with peak asymmetries in regions associated with language development and functional lateralization between 20 and 26 weeks' gestation. These patterns were validated in 1,487 three-dimensional brain volumes from 1,295 different fetuses in the same cohort. We provide a unique spatiotemporal benchmark of fetal brain maturation from a large cohort with normative postnatal growth and neurodevelopment

Radiological studies of fetal alcohol spectrum disorders in humans and animal models: an updated comprehensive review

Fetal Alcohol Spectrum Disorders encompass a wide range of birth defects in children born to mothers who consumed alcohol during pregnancy. Typical mental impairments in FASD include difficulties in life adaptation and learning and memory, deficits in attention, visuospatial skills, language and speech disabilities, mood disorders and motor disabilities. Multimodal imaging methods have enabled in vivo studies of the teratogenic effects of alcohol on the central nervous system, giving more insight into the FASD phenotype. This paper offers an up-to-date comprehensive review of radiological findings in the central nervous system in studies of prenatal alcohol exposure in both humans and translational animal models, including Magnetic Resonance Imaging, Computed Tomography, Positron Emission Tomography, Single Photon Emission Tomography and Ultrasonography. (C) 2017 Elsevier Inc. All rights reserved

Imaging the subthalamic nucleus in Parkinson’s disease

This thesis is comprised of a set of work that aims to visualize and quantify the anatomy, structural variability, and connectivity of the subthalamic nucleus (STN) with optimized neuroimaging methods. The study populations include both healthy cohorts and individuals living with Parkinson's disease (PD). PD was chosen specifically due to the involvement of the STN in the pathophysiology of the disease. Optimized neuroimaging methods were primarily obtained using ultra-high field (UHF) magnetic resonance imaging (MRI). An additional component of this thesis was to determine to what extent UHF-MRI can be used in a clinical setting, specifically for pre-operative planning of deep brain stimulation (DBS) of the STN for patients with advanced PD. The thesis collectively demonstrates that i, MRI research, and clinical applications must account for the different anatomical and structural changes that occur in the STN with both age and PD. ii, Anatomical connections involved in preparatory motor control, response inhibition, and decision-making may be compromised in PD. iii. The accuracy of visualizing and quantifying the STN strongly depends on the type of MR contrast and voxel size. iv, MRI at a field strength of 3 Tesla (T) can under certain circumstances be optimized to produce results similar to that of 7 T at the expense of increased acquisition time