MICA: Ultra-High Field MRI: Advancing Clinical Neuroscientific Research in Experimental Medicine

Magnetic Resonance Imaging (MRI) is a medical imaging technique that allows us to see detailed structure within the body and to measure the body's chemical environment. It has gained widespread use in hospitals and in medical research as a way of examining the whole body but it is particularly suited to visualizing brain structure and function. No other imaging technique gives as much information about the brain as MRI.

Many diseases affecting the brain are poorly understood; with their root cause unknown, good treatments often remain elusive. We propose to install a new 7 Tesla MRI system, requested in this application from the MRC, within the newly rebuilt and expanded Cardiff University Brain Research Imaging Centre (CUBRIC). This advanced MRI system would sit in alongside other brain imaging systems tailored to imaging microscopic tissue structure and the brain's electrical activity, making the combination of imaging equipment within the new CUBRIC unique in Europe. CUBRIC will also have a clinic in which new treatments can be tested and the way that the brain responds to these treatments will be measured using the brain scanners.

Using the 7T MRI system we will investigate the causes and treatments of brain conditions including psychiatric disorders such as schizophrenia, neurodegenerative conditions such as dementia, Parkinson's disease and Huntington's disease, neuroinflammatory conditions such as multiple sclerosis and conditions that can cause damage to the brain such as hypertension (high blood pressure). To understand better these conditions we will also need to study the healthy brain in detail across different age groups from young to old. A particular strength of Cardiff's proposed research will be in linking the discovery of genetic factors associated with brain disease to detailed assessments of brain structure and function made with the 7T MRI system. This will give us a clearer picture of underlying disease mechanisms that will in turn suggest new treatments that can be tried. 7T MRI will also give us sensitive ways of measuring whether a new treatment is working and so help us speed up the development of drugs and interventions to promote the brains own repair.

The main component of an MRI machine is the superconducting magnet within which the patient lies. From the beginnings of MRI there has been a trend towards using more powerful magnets that generate a stronger magnetic field (measured in Tesla, or T). Hospital MRI systems typically use 1.5T magnets while 3T is most common for research into the human brain. There are currently only two MRI systems in the UK that use 7T magnets, one at the University of Nottingham and the other at the University of Oxford. Cardiff's proposal for 7T MRI aims to use the benefits of this higher field strength to develop treatments and promote early and more refined diagnosis in patients. Higher magnetic field strengths in MRI bring strong benefits to brain research including:
1. increased signal such that we can speed up some imaging methods,
2. higher resolution images allowing us to see finer detail within the brain,
3. more sensitivity to detect naturally occurring chemicals in the brain that may be imbalanced when the brain malfunctions,
4. a much enhanced ability to detect changes in brain activity using a technique known as functional MRI
5. the ability to better measure blood flow to brain tissue
6. new forms of image contrast that give us previously unseen information about microscopic structure within the brain.
Together these technical advances in the MRI at 7T will give us a more complete window on to human brain structure and function.

The installation of 7T MRI in Cardiff would expand the UK's expertise in advanced neuroimaging. Cardiff would work closely with other UK centres in a new network known as UK7T to maximize the benefit to healthcare and UK industry of these investments in brain imaging technology.

Effective treatments remain elusive for many diseases affecting the central nervous system including neurodegenerative, neurodevelopmental, neuroinflammatory and psychiatric disorders. To advance experimental medicine in these areas better measurements of brain structure and function are needed to understand underlying disease mechanisms and to better stratify patient sub-groups with distinct disease mechanisms and treatment responses. Ultra-high field (7T) MRI offers a significant advance in brain imaging technology that can yield such measurements. Cardiff University is relocating and greatly expanding its Brain Research Imaging Centre (CUBRIC) in which it wishes to install 7T MRI alongside a bespoke microstructure-focused MRI system, MEG, EEG, TMS, tDCS, NIRS and a 1200 core computing cluster: a combination of neuroimaging hardware unique in Europe.

The requested support from the MRC for MRI hardware and complementary measurement technologies to optimize 7T MRI data quality and develop multi-modal imaging approaches will be augmented by large-scale support from Cardiff University for imaging methods-focused and clinical research fellows exceeding 24 person-years. Cardiff's investment in people will ensure speedy implementation of 7T MRI and development of imaging tools (for example, quantitative functional brain imaging, susceptibility based contrasts, enhanced MR spectroscopy and multi-nuclear imaging) and their rapid translation to clinical neuroscientific research. This will have a particular focus on connecting gene discovery and genomics to specific imaging signals and thus providing mechanistic insights that can guide the development of new treatments. This work in conditions such as schizophrenia will exploit the substantial expertise in this area in the Cardiff MRC Centre for Neuropsychiatric Genetics and Genomics. Cardiff will maximise the speed of clinical impact by working closely with existing and new 7T centres in the proposed new UK7T network.

This proposal will build UK ultra-high field (7T) MRI clinical research capacity in Experimental Medicine, aiming to identify disease mechanisms and demonstrate proof-of-concept treatment validity, and in Stratified Medicine approaches that improve clinical trials by identifying patient sub-groups with distinct disease mechanisms or treatment responses. Researchers in these fields will benefit from advances delivered by this proposal, allowing the UK and international research base to grow. Other key stakeholders will be the ultimate beneficiaries including patients, healthcare services and industry.

Impact on Patients:
The work in this proposal will benefit patients with a range of neurological and psychiatric diseases, by improving our understanding of disease mechanisms, demonstrating and guiding new treatments and providing tools for early and better diagnosis, in:
1) Psychiatric conditions such as Schizophrenia, via enhanced structural MR markers and MRS (GABA/Glutamate) at 7T.
2) Other mental health conditions such as depression, via enhanced MRI/FMRI/MRS markers and neurofeedback intervention techniques at 7T.
3) Dementia, both Alzheimer's and vascular, by understanding neurodegenerative disease processes.
4) Multiple-sclerosis via enhanced structural and metabolic MR.
5) Huntington's disease via better targeting of repair strategies and monitoring of interventions such as stem-cell implantation.
6) Epilepsies (such as temporal-lobe), via enhanced MRI/FMRI/MRS of pathology and better surgical planning leading to better patient outcomes.
7) Cerebrovascular disease, such as associated with hypertension, via imaging vascular function and brainstem mechanisms at 7T.

A deeper understanding of their disorder is important to patients. We will support regular discussion and dissemination of results from clinical studies to the patient populations. We will achieve this via regular accessible seminars, which will be held to inform patients (and interested members of the public) about results from our studies. In addition, all of our clinicians have good links to patient stakeholder groups and will use these to consult/disseminate findings from the work in this proposal.

Impact on industry:
The development of new drugs in psychiatry and neruology is extremely expensive leading to sector-wide attempts to reduce costs. A particular focus is the development of early markers of drug action for stratified patient groups and for predicting an individual's response. The work in this proposal, utilizing the ability of 7T to deliver new and enhanced MR markers, has the capacity to deliver significant impact in this area, as evidenced by our pharmaceutical partners in this bid: GlaxoSmithKline, Lilly, the P1Vital consortium and the University of Sussex's Translational Drug Discovery Group. Outside pharma, there are also significant opportunities for medical devices companies to enhance competitiveness by developing products for the emerging 7T market. This includes our project partners, Magstim, PulseTeq and the MR vendors. We will maximize impact in this context by ensuring tight integration of all of these partners into our work, including through the use of co-funded research projects.

Impact on government and the NHS:
We will work closely with the NISCHR-funded National Centre for Mental Health (NCMH) Wales and Cardiff and Vale NHS Neurosciences to promote clinical trials, ensuring a pathway for direct pull-through to the NHS. The 7T MRI work in this proposal will also provide strong support for a bid to the Welsh Government to enhance genomic medicine infrastructure in Wales.

The General Public:
Cardiff University in general, and Neuroscience in particular, has strong outreach programmes that are aimed towards making the results of scientific studies accessible to a broad non-academic audience. We will use these pre-existing pathways to ensure rapid and engaging dissemination of our work to the public.