Cardiff University-Equipment Account

MRI scanners are used widely to diagnose disease and to understand the workings of the healthy body. However, while useful for some diagnoses, they do not capture tissue properties at microscopic length scales (thousandths of a millimetre) where important processes occur, e.g. in the 'axons' connecting different brain areas, or in cells in vital organs, e.g. liver. Such detailed examination usually requires an invasive 'biopsy' which is studied under a microscope. However, biopsies only provide information about small regions of an organ, are destructive and so cannot be performed repeatedly for monitoring, and can be risky to collect, e.g. in the brain.

This project assembles engineers, physicists, mathematicians and computer scientists to develop new MRI methods for quantifying tissue structure at the microscopic scale. The principal approach looks at how fine tissue structure impedes the movement of water. Current MRI hardware restricts measurement to relatively large molecular displacements and from tissue components with a relatively strong and long-lived signal. This blurs our picture and prohibits us from quantifying important characteristics, such as individual cell dimensions, or packing of nerve fibres.

The sensitivity of MRI to smaller molecular movements and weaker signals is mainly limited by the available magnetic field gradients (controlled alterations in the field strength within the scanner). We have persuaded MRI manufacturers to build a bespoke MRI system with ultra-strong gradients (7 times stronger than available on standard MRI scanners) to be situated in the new Cardiff University Brain Research Imaging Centre. One similar system currently exists (in Boston, USA) but is used predominantly to make qualitative pictures of the brain's wiring pattern. Our team has the unique combination of expertise to develop and exploit this hardware in completely new directions. By designing new physics methods to 'tune' the scanner to important (otherwise invisible) signals, developing new biophysical models to explain these signals, and suppressing unwanted signals, we will be able to quantify important tissue properties for the first time.

Making such a system usable poses several key engineering challenges, such as modelling of electromagnetic fields, to deal with confounds that become significant with stronger gradients, and modelling of the effects on nerves/cardiac tissue, to impose safety constraints. However, the current work of the consortium of applicants provides strong starting points for overcoming these challenges. Established methods for accelerating MR data acquisition will be compromised with stronger gradients, requiring development of new physics methods for fast data collection. Once achieved, faster acquisition and access to newly-visible signal components will enable us to develop new mathematical models of microstructure incorporating finer length-scales to increase understanding of tissue structure in health and disease, and to make testable predictions on important biophysical parameters such as nerve conduction velocities in the brain. This will result in earlier and more accurate diagnoses, more specific and better-targeted therapy, improved treatment monitoring, and overall improved patient outcome. The ultimate goal is to develop the imaging software that brings this hardware to mass availability, in turn enabling a new generation of mainstream microstructure imaging and macrostructural connectivity mapping techniques to translate to frontline practice.

A National Microstructure Imaging Facility will impact positively on a wide range of stakeholders that can put to important uses new, more sensitive medical imaging tools. This is directly in line with the EPSRC's Healthcare Technologies theme, particularly with respect to enhancing prediction and diagnosis and the technology to develop new biomarkers.

MR scanner manufacturers will benefit by extending MRI into new territory and clinical applications, setting new standards for a future generation of clinical hardware. Moreover, manufacturers and users will benefit through future exploitation on standard MR scanners of the new techniques and engineering solutions developed in order to bring the NMIF into operation.

Once the core technology is developed, diseases with a particularly high societal burden, including dementia and cancer, will be early targets for clinical translation and therefore rapid impact.

We have identified key industrial partnerships that will accelerate benefits to industry, particularly in the UK, focusing on the medical device and pharmaceutical industries.
These partnerships will precipitate bringing putative treatments to market, with subsequent major impact on the UK economy as well as the well-being of patients and carers.

The new methods will provide sensitive biomarkers of dementia promoting early diagnosis and the improved stratification of patient groups. This impact is exemplified by our partnership with Acuitas Medical which aims to use the high-gradient system to identify dementia-related changes in microstructural columns within the brain. The techniques we develop will aim to detect subtle microstructural changes in tumour cells, helping to diagnose cancer and monitor treatment response, allowing better therapeutic decision making and replacing the biopsy. The ultimate goal is earlier and more accurate diagnoses, more specific and better-targeted therapy, improved treatment monitoring, and overall improved patient outcome.

There is a pressing need for more sensitive and specific biomarkers in the pharmaceutical industry to reduce development costs by providing early signals of drug efficacy and allowing the most promising compounds to be taken forward in development as rapidly as possible. This will lead to more treatments to more patients more quickly. We will partner with GlaxoSmithKline, the UK's largest pharmaceutical company, to develop imaging markers useful in drug development. We will partner with Renishaw to improve models and software for neurosurgery and drug and stem cell delivery into the brain, accounting for the impact of tissue microstructure on the transport of the drug/cells.

Magstim, a world leading manufacturer of electromagnetic (EM) brain stimulation equipment, will partner with the NMIF. Modelling of the EM properties of tissue, using the microstructural measurements, will allow the company to improve both their coil designs and paradigms for brain stimulation.

The benefits to medical device and pharmaceutical research are likely to be realized in the next 3-5 years with the initiation of early clinical trials. The wider benefits to routine measurements would naturally take longer to realise, typically 5+ years. In addition, the NMIF and the associated research and industrial network will produce a professional training opportunity unparalleled in Europe producing highly skilled imaging methodologists to work in research and industry.

Finally, we will partner with the UK arts community to engage the public in our science, benefitting the scientists themselves (gaining new insights through two-way interaction), the artists (gaining new inspiration for their work), the museums and art galleries that will host the travelling exhibitions and members of the public that attend the exhibitions.