Our research on microstructure imaging has the ultimate goal of non-invasive histology. Classical histology uses a microscope to visualize the cellular architecture of tissue from a thinly sliced sample mounted on a slide. Histology provides the gold-standard diagnosis for a wide range of diseases from cancers to dementias. However, it requires a tissue sample from a biopsy or taken post mortem. The idea of non-invasive histology is to obtain the same information that a histologist gets from microscope images from non-invasive imaging techniques such as magnetic resonance imaging (MRI). The non-invasive nature of microstructure imaging avoids patient discomfort and possible side effects of standard biopsy-histology procedures and enables temporal monitoring through repeat measurements. Moreover, microstructure imaging produces maps over whole organs rather than a targeted biopsy sample of a few mm3, so is less prone to false negatives from poor targeting, and provides a more complete picture of heterogeneous diseases, such as cancer.
How do we do it?
In a nutshell
Microstructure imaging works by fitting mathematical models of cellular architecture to imaging data. Most of our work uses diffusion MRI, but other kinds of measurement can contribute. We solve an inverse problem in each image voxel to estimate and map histological tissue parameters; the figure below shows an example from the ActiveAx technique, which maps features of white matter such as axon diameter and density.
Where are we?
In a nutshell
We have developed a range of “multiple-fibre reconstruction” or “high angular resolution diffusion imaging (HARDI)” techniques for estimating fibre orientations and configurations from diffusion MRI enabling non-invasive studies of brain connectivity through tractography. Most of that work was with the support of the EPSRC Multiple Fibre Reconstructions project.
We have two primary working microstructure imaging techniques: ActiveAx and NODDI (Neurite Orientation Dispersion and Density Imaging), both designed for brain imaging. ActiveAx uniquely maps orientationally invariant axon diameter and density indices, as shown in the figure at the top of this page. It works very well on fixed brain samples that we can image for a long time with powerful scanners and is rapidly gaining popularity for these applications. Although, we have demonstrated ActiveAx on live human volunteers, the imaging time is close to one hour and the axon-diameter contrast remains weak. We aim to gain clinical applicability in the near future by exploiting faster acquisition to reduce scan time and specialized diffusion-weighted pulse sequences to increase sensitivity. NODDI produces separate maps of dispersion of fibre orientations (how much fanning/bending/etc), fibre density, and partial volume with free water (e.g. cerebro-spinal fluid). The traditional fractional anisotropy (FA) index from diffusion tensor imaging (DTI) confounds these three effects; NODDI allows separate analysis of each. The technique also provides useful information in grey matter, such as the dispersion and density of the dendritic tree. NODDI requires only 10-30 mins acquisition time with standard pulse sequences so is clinically feasible. Both techniques were developed within the EPSRC Direct Measurements of Microstructure from MRI and EU CONNECT projects and open-source post-processing code is available for both.
How is it useful?
In a nutshell
Target clinical applications include dementias, such as Alzheimer’s disease, multiple sclerosis, epilepsy, and a range of other neurological conditions. Many neurological diseases have hallmark histopathology such as neuronal loss, axonal degeneration, amyloid plaque deposition, and neurofibrillary tangles, which can affect image intensities in different ways potentially allowing microstructure imaging techniques to detect them and grade their severity. Another key application is solid cancers, such as prostate cancer, brain tumours, and breast cancer. Different grades of cancer have different cellular architecture, for example more malignant tumours often have higher cellularity (cell density) than benign. Again such features are amenable to the microstructure imaging approach, which we hope will lead to clinical diagnostic imaging techniques in the near future.
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