Next generation MRI technologies for measuring brain oxygen metabolism

The revolution of imaging the function of the brain using MRI, rather than just its structure, was kick started by the discovery of the blood oxygenation level dependent (BOLD) effect more than twenty years ago. As its name suggests this effect is dependent on blood oxygenation and is therefore sensitive to the rate at which the brain is consuming energy by burning glucose and oxygen (oxygen metabolism). Whilst BOLD functional MRI (fMRI) has enabled great improvements in our knowledge about the localisation of function it remains a qualitative measure of brain activity. By measuring oxygen metabolism we can take a direct look at the metabolic workload required to sustain this brain activity. Quantitative measurements of oxygen metabolism are possible using two techniques: calibrated BOLD and quantitative BOLD. Unfortunately neither method has reached its full potential. This is due in part to the complexity of these methods and requirements to perform complicated breathing challenges involving carbon dioxide. In both cases specialist knowledge is required, limiting the application of these methods to a small number of methodological research centres. The aim of this proposal is to remove these barriers enabling a broad spectrum of users to take advantage of these methods.

Calibrated BOLD enables changes in oxygen metabolism, which are caused by performing a task or experiencing a stimulus, to be measured. However, in the current implementation of this method the participant must breathe air with added carbon dioxide. As well as the discomfort this causes, such experiments are difficult and time consuming to set up. In this proposal this so-called 'calibration' will be replaced by a simple measurement of the intrinsic relaxation properties of tissue. At a stroke, the set up of complicated equipment is removed and gas breathing is no longer required. This technique has the potential to be a required part of every fMRI experiment as it enables changes in baseline physiology to be obtained in a simple and quick manner. Such changes in baseline physiology between subjects and sessions can confound the interpretation of fMRI experiments leading to incorrect inferences.

Quantitative BOLD enables resting baseline oxygen metabolism to be estimated by measuring the amount of oxygen extracted to serve metabolism (oxygen extraction fraction). The method relies on the theoretical understanding that the intrinsic relaxation properties of tissue are dependent on the total amount of deoxygenated haemoglobin that is present in the pixel being imaged. This is effectively dependent on the product of the blood volume and the oxygen extraction fraction. Therefore an accurate measurement of blood volume is critical for disentangling these effects. Currently this is achieved using a subtle signal variation predicted by theory. In this proposal blood volume will be measured using oxygen as a tracer. This new technique has the potential to realise much higher accuracy and reproducibility than the current method. It also fulfils an unmet need of the healthcare community: a measurement of resting oxygen metabolism. The only other established method to achieve this uses Positron Emission Tomography (PET). However, this method requires the use of three radioactive tracers and the associated dose of ionising radiation. The expense and complexity of this method means that there are very few sites within the UK that are able to perform such experiments. In contrast, MRI is widely available and most clinical sites have direct access to 100% oxygen within the imaging suite. Hence this method has the potential to vastly improve the diagnostic capability of the UK healthcare system at minimal expense.

The research proposed in this application is predicted to impact a range of non-academic beneficiaries over the shorter and longer term. Short term benefits may include the development of improved BOLD methodologies that can be quantified in terms of oxygen metabolism. These will be achieved over the course of the study. The validation of these technologies will provide improved diagnostic methods and biomarkers of drug action. This could result in changes to clinical practice and facilitate drug discovery. However, such impacts are likely to be achieved over the longer term

Patients, carers and families, the broader care community, research supporters/donors
- Availability of improved BOLD methodologies for diagnosis in e.g. in ischaemic stroke but potentially a wide range of CNS disorders e.g. haemorrhagic stroke, chronic pain, neurodegenerative and psychiatric disease.
- Removes the necessity to undergo an uncomfortable respiratory challenge.
- Potential improvements in use of anaesthesia in clinical practice
- Potential for novel BOLD methodologies to facilitate the development of novel therapies for CNS disorders.

UK and international biotech/pharmaceutical industry
- Development of biomarkers of brain oxygen metabolism to support drug discovery for CNS disorders.
- Development of novel software for medical imaging companies.
- Potential to reposition drugs that have failed to provide efficacy in other conditions thus recovering R&D expenditure and increasing revenue.

UK NHS/funding agencies
- Ability for measuring brain oxygen metabolism in normal fMRI centers.
- Availability of biomarkers/diagnostic tests to predict course of CNS disease and treatment options.
- Potential development of novel biomarkers to support clinical research/experimental medicine.

The broader UK economy
- Stimulating growth in development of novel treatments for CNS disorders and area from which pharma has withdrawn in recent years.
- Potentially new therapies for CNS disorders, thus reducing cost of caring for patients, supporting patients unable to work and reducing loss to economy due to loss of productive work years.