National Facility for In Vivo MR Imaging of Human Tissue Microstructure

Magnetic Resonance Imaging (MRI) scanners are used throughout the world to image the human body in hospitals and for research. They are used to diagnose disease and to understand the workings of the healthy body. In clinical settings, MRI scanners most often collect images which show objects down to about 1 mm in size. These are useful for some diagnoses, but are unable to capture tissue properties at microscopic length scales (thousandths of a millimetre), at which important processes may occur, e.g. in the 'axons' (the cells forming connections between different brain areas), or in cells in vital organs, such as the liver or kidney. Such detailed examination usually requires a 'biopsy' to remove tissue which is then examined under a microscope. However, biopsies only look at a tiny sample of tissue and can be risky to collect, e.g. in the brain.

This project will develop MRI in new ways to quantify tissue structure at the microscopic scale. The principal method looks at how water molecules moving in the body are impeded by fine structure within the tissue. While diffusion MRI has existed for 30 years, current MRI machines restrict us to measuring only relatively large molecular movements. This blurs our picture of the tissue, prohibiting us from looking at important characteristics, such as the dimensions of individual cells, or the density or packing of nerve fibres.

The main factor that can sharpen the picture, by sensitising MRI to smaller molecular movements, is a substantial increase in magnetic field gradients. These gradients are controlled alterations in the magnetic field strength within the MRI scanner. We will partner with a scanner manufacturer to create a system that produces gradients about 7 times stronger than available on standard MRI machines. There is only one similar system anywhere else in the world (in the USA) and we therefore propose to establish a 'National Facility for the In Vivo Imaging of Tissue Microstructure' here in the UK, serving as a national hub for development and application of advanced microstructural imaging methods.

Our first scientific aim will be to achieve robust and reliable measurements. We will develop methods to reduced the impact of inevitable imperfections in the hardware, and the effects of the person moving during scanning. About 75% of the project will be spent developing novel engineering and physics methods to obtain the best possible measurements. The increased sensitivity will allow us to characterise tissue in a range of organs to an unprecedented level of detail. In the brain, the white matter is the 'wiring' that interconnects different regions and is affected in many diseases including dementia, Alzheimer's disease, schizophrenia, depression and multiple sclerosis. Measurements on standard hardware lack the ability to show exactly how white matter is affected by these diseases, but at the NMIF we will be able to distinguish any changes in the shape or size of the axons (the tube-like structures), from changes in the myelin (the fatty insulation layer that wraps around axons). This will allow us to make better predictions about the white matter's ability to carry information. In cancer, we aim to replace the tumour biopsy with advanced microstructural imaging, being able to quantify non-invasively cell size, and density. The ultimate goal is to provide earlier and more accurate diagnoses, more specific and better-targeted therapy, improved treatment monitoring and overall improved outcome for patients with a range of debilitating diseases.

The project will develop and benefit from academic and industrial research partnerships in the UK and internationally. There is great potential for application in drug development, a strong industrial sector in the UK, for the development and delivery of new and effective treatments. This project will help maintain the UK's longheld position at the the international forefront of neuroimaging research.

Our proposal to establish the UK's National Microstructure Imaging Facility (NMIF) would benefit a wide range of stakeholders that can put to important uses new and more sensitive medical imaging tools.

Basic biological and clinical researchers would benefit from the non-invasive imaging tool that can be applied to living humans. It will allow them to address their research questions over the structure and function of the human body in a way that has only been possible previously with invasive sampling of tissue through biopsy. Longitudinal clinical studies become possible examining the fine structure of human organs as they develop, age and change with disease. This benefits researchers and clinicians focusing on, for example brain, heart, muscles, kidney, prostate, liver bone and bowel. The subsequent healthcare and economic benefits are, therefore, substantial. Diseases with a particularly high societal burden, including dementia and cancer, will be an early target for clinical translation and therefore rapid impact. Commonly, in cancer, tumour cells are organized differently with respect to normal healthy tissue. The techniques we develop within the NMIF will aim to detect such subtle microstructural changes, helping to diagnose cancer and monitor treatment response, allowing better therapeutic decisions to be made.

The new imaging methods developed at the NIMF will provide sensitive biomarkers of dementia in the brain promoting its early diagnosis and the improved stratification of patient groups. Perhaps more pressing is the need for tools to help understand the basic pathology of dementia in the living brain and therefore to drive the development and accelerated testing of new treatments. This potentially rapid 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.
We have already identified key industrial partnerships that will accelerate benefits to industry, particularly in the UK, focusing on the medical device and pharmaceutical industries. Renishaw will be working with us to model brain tissue structure and produce improved software tools for drug delivery neurosurgery. There is a pressing need for more sensitive and specific biomarkers in the pharmaceutical industry to reduce the costs of development 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, on the NMIF project to develop imaging markers useful in drug development. The MR scanner manufacturers are likely to benefit by extending MRI into new territory and new clinical applications, setting a new standard for a future generation of clinical hardware. Magstim will exploit the NMIF to improve 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 to the direct scientific benefits 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, our proposal includes plans to engage with the UK art community to engage the public in our science. There are many beneficiaries to this, including 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 exhibition, and the public that attends the exhibitions.