Penny L. Hubbard

Orientationally invariant indices of axon diameter and density from diffusion MRI

This paper proposes and tests a technique for imaging orientationally invariant indices of axon diameter and density in white matter using diffusion magnetic resonance imaging. Such indices potentially provide more specific markers of white matter microstructure than standard indices from diffusion tensor imaging. Orientational invariance allows for combination with tractography and presents new opportunities for mapping brain connectivity and quantifying disease processes. The technique uses a four-compartment tissue model combined with an optimized multishell high-angular-resolution pulsed-gradient-spin-echo acquisition. We test the method in simulation, on fixed monkey brains using a preclinical scanner and on live human brains using a clinical 3T scanner. The human data take about one hour to acquire. The simulation experiments show that both monkey and human protocols distinguish distributions of axon diameters that occur naturally in white matter. We compare the axon diameter index with the mean axon diameter weighted by axon volume. The index differs from this mean and is protocol dependent, but correlation is good for the monkey protocol and weaker, but discernible, for the human protocol where greater diffusivity and lower gradient strength limit sensitivity to only the largest axons. Maps of axon diameter and density indices from the monkey and human data in the corpus callosum and corticospinal tract reflect known trends from histology. The results show orientationally invariant sensitivity to natural axon diameter distributions for the first time with both specialist and clinical hardware. This demonstration motivates further refinement, validation, and evaluation of the precise nature of the indices and the influence of potential confounds.

Axon diameter mapping in the presence of orientation dispersion with diffusion MRI

Direct measurement of tissue microstructure with diffusion MRI offers a new class of markers, such as axon diameters, that give more specific information about tissue than measures derived from diffusion tensor imaging. The existing techniques of this kind assume a single axon orientation in the tissue model, which may be a reasonable approximation only for the most coherently oriented brain white matter, such as the corpus callosum. For most other areas, orientation dispersion is not negligible and, if unaccounted for, leads to overestimation of the axon diameters, prohibiting their accurate mapping over the whole brain. Here we propose a new model that captures the effect of orientation dispersion explicitly. A numerical scheme is developed to compute the diffusion signal prescribed by the proposed model efficiently, which supports the simultaneous estimation of the axon diameter and orientation dispersion. Synthetic data experiments demonstrate that the new model provides an axon diameter index that is robust to the presence of orientation dispersion. Results on in vivo human data show reduced axon diameter index and better agreement with histology compared to previous methods suggesting improvements in the axon diameter estimate.

Biomimetic phantom for the validation of diffusion magnetic resonance imaging

A range of advanced diffusion MRI (dMRI) techniques are currently in development which characterize the orientation of white matter fibers using diffusion tensor imaging (DTI). There is a need for a physical phantom with microstructural features of the brains white matter to help validate these methods.

Z-spectroscopy with Alternating-Phase Irradiation

Magnetization transfer (MT) MRI and Z-spectroscopy are tools to study both water-macromolecule interactions and pH-sensitive exchange dynamics between water and the protons of mobile chemical groups within these macromolecules. Both rely on saturation of frequencies offset from water and observation of the on-resonance water signal. In this work, an RF saturation method called Z-spectroscopy with Alternating-Phase Irradiation (ZAPI) is introduced. Based on the T(2)-selectivity of the irradiation pulse, ZAPI can be used to separate the different contributions to a Z-spectrum, as well as to study the T(2) distribution of the macromolecules contributing to the MT signal. ZAPI can be run at resonance for water and with low power, thus minimizing problems with specific absorption rate (SAR) limits in clinical applications. In this paper, physical and practical aspects of ZAPI are discussed and the sequence is applied in vitro to sample systems and in vivo to rat head to demonstrate the method.

Validation of Tractography

Publisher Summary The validation of tractography is fundamental to the implementation of the technique as a useful biomedical tool. The technique has the potential to help in the diagnosis of patients suffering from brain injury and disease, as well as providing insights into basic neuroscience. It discusses the studies of simple biological models, in which the complexity is increased at the expense of a decrease in control of the underlying architecture and knowledge of the ground truth. Comparison of tractography results with those of invasive tract tracing techniques returns some degree of ground-truth knowledge, allowing the methodology to be tested in vivo and in the brain; however, the invasiveness of dissection studies means that these methods can only be used in animal studies. Yet it is humans that are ultimately the subjects on which the fiber tracking techniques must be validated. The use of known anatomy is an integral part of the validation process, as is the use of circumstantial validation in the form of functional imaging and lesion studies. The search for a “gold standard” for tractography is the search for an ideal model that possesses true axonal characteristics, combined with an ideal model of signal generation—as yet no suitable software or physical phantom has been created. However, a range of work has been reported in which the attributes and pitfalls of the assortment of fiber tracking methodology have been both qualitatively and quantitatively assessed, and which provides valuable information regarding the reliability of the tractography process. The potential of tractography to map the three-dimensional network of connections between brain regions in a non-invasive manner is one of the most exciting recent developments in neuroimaging.

Coaxially electrospun axon-mimicking fibers for diffusion magnetic resonance imaging.

The study of brain structure and connectivity using diffusion magnetic resonance imaging (dMRI) has recently gained substantial interest. However, the use of dMRI still faces major challenges because of the lack of standard materials for validation. The present work reports on brain tissue-mimetic materials composed of hollow microfibers for application as a standard material in dMRI. These hollow fibers were fabricated via a simple and one-step coaxial electrospining (co-ES) process. Poly(ε-caprolactone) (PCL) and polyethylene oxide (PEO) were employed as shell and core materials, respectively, to achieve the most stable co-ES process. These co-ES hollow PCL fibers have different inner diameters, which mainly depend on the flow rate of the core solution and have the potential to cover the size range of the brain tissue we aimed to mimic. Co-ES aligned hollow PCL fibers were characterized using optical and electron microscopy and tested as brain white matter mimics on a high-field magnetic resonance imaging (MRI) scanner. To the best of our knowledge, this is the first time that co-ES hollow fibers have been successfully used as a tissue mimic or phantom in diffusion MRI. The results of the present study provide evidence that this phantom can mimic the dMRI behavior of cellular barriers imposed by axonal cell membranes and myelin; the measured diffusivity is compatible with that of in vivo biological tissues. Together these results suggest the potential use of co-ES hollow microfibers as tissue-mimicking phantoms in the field of medical imaging.

Chapter 20 – Validation of Tractography

This chapter leads the reader through the scaffold of validation studies that have been carried out with the aim of supporting tractography. We start with software and physical phantoms, which are user-definable and easy to manipulate, but are gross approximations of the in vivo brain. We then discuss simple biological models, in which complexity is increased at the expense of decreased control of underlying architecture and ground truth. Comparing tractography with invasive tract-tracing techniques returns some degree of ground-truth knowledge, allowing testing in the in vivo brain. However, the invasiveness of dissection studies and the potential toxicity of classical histological and MR-visible tracers, means these methods can only be used in animals. It is humans that are ultimately the subjects on which fiber tracking must be validated. The use of known anatomy and circumstantial validation, such as functional imaging and lesion studies, is an integral part of the validation process.