Next generation MRI technologies for measuring brain oxygen metabolism

Lead Research Organisation: University of Oxford
Department Name: Clinical Neurosciences

Abstract

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.

Planned Impact

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.

Publications

10 25 50
 
Description This study is largely methodological in nature with the aim of developing new tools for the measurement of oxygen metabolism in human subjects or patients.

To date we have developed a new technique that is sensitive to blood oxygenation in the brain, but not other sources of signal caused by imperfections in the MRI magnetic field. We have used this new technique to measure oxygen metabolism in the brain, whilst marginalising confounding sources of signal, and we have tested this technique in a cohort of healthy subjects. We have now completed a proof of concept study in acute stroke patients with very positive results. We hope that this method will help clinicians understand the progression of stroke and in the longer term inform treatment decisions. We are also investigating the utility of our technique in traumatic brain injury, subarachnoid haemorrhage and brain tumour.

In addition we continue to pursue development of a technique to measure changes in oxygen metabolism following a stimulus. Such a technique would be very useful in neuroscientific applications. We are currently investigating the problems with the conventional approach with a view to making future comparisons with our new improved technique.
Exploitation Route We will continue to collaborate with clinical colleagues to improve the effectiveness of our new technique and to examine its utility in the treatment of stroke. Further methodological research is required to expand the number of applications this technique can be used in and to improve its sensitivity. Open data and code will facilitate other researchers building upon our work.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description We have had interest in these techniques from other laboratories and companies. In particular we have worked with researchers from other institutions both within the UK (Cardiff University, Brighton and Sussex Medical School) and internationally (University of Calgary, UCSD) to further develop these techniques. In addition during regular meetings with our industrial collaborator Siemens Healthineers we are able to discuss our portfolio of techniques. We have acquired measurements of resting oxygen metabolism in patients with acute stroke, traumatic brain injury, subarachnoid haemorrhage and brain tumour. It is possible that this could have impact in the care of such patients. We are also collaborating with neuroscientists interested in anaesthesia to better understand loss of consciousness, which may also improve human health.
Sector Healthcare
 
Title A tool for investigating systematic bias in BOLD based MRI methods: An implementation of the detailed BOLD signal model 
Description Simulation code was developed to investigate sources of systematic bias in calibrated BOLD functional MRI (fMRI) based mapping of the oxygen extraction fraction. However, this tool may be useful for improving our understanding of other BOLD based fMRI methods. 
Type Of Material Computer model/algorithm 
Year Produced 2015 
Provided To Others? Yes  
Impact Simulation code has been used by collaborators at Cardiff University in the following publication (Merola A, Murphy K, Stone AJ, Germuska MA, Griffeth VEM, Blockley NP, Buxton RB, Wise RG. Measurement of oxygen extraction fraction (OEF): An optimized BOLD signal model for use with hypercapnic and hyperoxic calibration. Neuroimage 2016;129:159-174. doi: 10.1016/j.neuroimage.2016.01.021.) 
URL https://ora.ox.ac.uk/objects/uuid:cbee3305-4b21-4445-b2e0-5f86187c82d6
 
Title Data acquired during the development of an R2' mapping technique with prospective correction for macroscopic magnetic field gradients 
Description The data in this archive was acquired during the development of the GASE (Gradient-Echo Slice Excitation Imaging Asymmetric Spin Echo; GESEPI ASE) technique. GASE can be used to map the reversible transverse relaxation rate R2' (a contrast used in Magnetic Resonance Imaging - MRI) without the need to separately acquire a magnetic field map to correct for residual magnetic field gradients not compensated by magnet shimming. This technique has application in measuring blood oxygenation using the quantitative BOLD (baseline levels) and calibrated BOLD (dynamic changes) techniques as well as iron deposition. 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
Impact None to date. Has been downloaded 31 times. 
URL https://ora.ox.ac.uk/objects/uuid:fe4cf726-24e1-4bc3-bc24-5c246515d131
 
Title Data acquired to demonstrate a streamlined approach to mapping and quantifying brain oxygenation using quantitative BOLD 
Description Data associated with publication (Stone AJ, Blockley NP. A streamlined acquisition for mapping baseline brain oxygenation using quantitative BOLD. Neuroimage 2017;147:79-88. doi: 10.1016/j.neuroimage.2016.11.057.) 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
Impact None to date. 
URL https://ora.ox.ac.uk/objects/uuid:177afade-8599-4d9c-959e-26e1426ec486
 
Title Data acquired to demonstrate model-based Bayesian inference of brain oxygenation using quantitative BOLD 
Description This dataset will form the basis of a forthcoming publication regarding a model-based Bayesian analysis of streamlined quantitative BOLD data to measure brain oxygenation. 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
Impact None so far. 
 
Title Data acquired to investigate new approaches to cerebrovascular reactivity mapping using MRI 
Description Data related to a forth coming publication. 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
Impact None to date. 
URL https://doi.org/10.5287/bodleian:Xk48adQAO
 
Title Data generated by a Monte Carlo based simple vessel simulation of the ASE qBOLD signal 
Description The data in this archive was generated using a Monte Carlo based numerical simulation of the extravascular blood oxygenation level dependent effect (BOLD) MRI signal. 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? Yes  
Impact None so far 
 
Title Data used to investigate the application of streamlined-quantitative BOLD (sqBOLD) in acute stroke. 
Description This dataset was acquired to investigate the application of sqBOLD to imaging baseline brain oxygenation in acute stroke. Data was acquired as part of an ongoing study where a prospective cohort of patients with acute ischaemic stroke were imaged on presentation with follow-up scanning performed at 2 hours, 24 hours, 1 week and 1 month where available. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact None so far. 
URL https://doi.org/10.5287/bodleian:VYmwzrzpd
 
Description Measuring oxygen metabolism using an asymmetric spin echo 
Organisation Cardiff University
Country United Kingdom 
Sector Academic/University 
PI Contribution Support with implementation of asymmetric spin echo on partners MRI scanner. Advice and support with theoretical and methodological aspects of the project.
Collaborator Contribution Application of the method using partners automated gas delivery system for accurate hyperoxia gas administration to human subjects.
Impact Paper in preparation
Start Year 2013
 
Description Simulating dcFMRI using a detailed model of the BOLD signal 
Organisation Cardiff University
Department Brain Research Imaging Centre (CUBRIC)
Country United Kingdom 
Sector Academic/University 
PI Contribution Supplied computer simulation tools and advice/support with its application
Collaborator Contribution Cardiff University - Applied the simulation code supplied by myself and my UCSD partners to investigate their dcFMRI method UCSD - supplied computer simulation tools and advice/support with its application
Impact This collaboration has resulted in the publication of one paper (http://dx.doi.org/10.1016/j.neuroimage.2016.01.021).
Start Year 2014
 
Description Simulating dcFMRI using a detailed model of the BOLD signal 
Organisation University of California, San Diego (UCSD)
Country United States 
Sector Academic/University 
PI Contribution Supplied computer simulation tools and advice/support with its application
Collaborator Contribution Cardiff University - Applied the simulation code supplied by myself and my UCSD partners to investigate their dcFMRI method UCSD - supplied computer simulation tools and advice/support with its application
Impact This collaboration has resulted in the publication of one paper (http://dx.doi.org/10.1016/j.neuroimage.2016.01.021).
Start Year 2014
 
Description Simulating the asymmetric spin echo signal to improve estimates of oxygen metabolism 
Organisation University of Calgary
Country Canada 
Sector Academic/University 
PI Contribution I provided know-how surrounding a technique I developed to estimates changes in oxygen metabolism that result from neuronal stimulus. As my collaborator developed his new technique I provided regular feedback.
Collaborator Contribution My collaborator provided detailed simulations of my technique and developed an improved method. I was able to use his simulation technique to further develop my own work on resting oxygen metabolism.
Impact This collaboration has resulted in a publication (https://doi.org/10.1016/j.neuroimage.2017.12.047).
Start Year 2014
 
Description PPI with Dementia patients and their families 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact We attended an Alzheimer's society Dementia Cafe to talk about our work with patients and their families. Five or six couples attended plus support staff from the Alzheimers society. We gained valuable insight into how to improve our MRI techniques in the future.
Year(s) Of Engagement Activity 2017
 
Description Primary school visits 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I visit Uffington C of E Primary school to assist in the delivery of science teaching as part of their gifted and talented programme. So far these events have involved me discussing scientific principles with pupils, designing practical demonstrations and performing scientific experiments. These visit are always very interactive. The children have lots of ideas and I hope the presence of a working scientist serves to inspire them to pursue a career in a STEM subject.
Year(s) Of Engagement Activity 2014,2015
 
Description STEM Ambassador 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The STEM ambassador programme is a scheme to train scientists to engage with schools. This is an ongoing activity, but has so far resulted in two schools visits.
(1) Can we take pictures of our brains? - presentation to year 1 (3 classes)
(2) What does a Scientist do? - presentation to Foundation class
Year(s) Of Engagement Activity 2016