Towards Quantitative fMRI for Serial Studies of the Normal and Diseased Brain

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

Abstract

The relatively new technique of functional magnetic resonance imaging (fMRI) has provided a uniquely non-harmful way of studying the way the human brain works. We are able to use this technology to study both healthy people, and people with brain diseases. To date, however, it has been difficult to make rigorous comparisons of brain activity in the same person across different points in time (for example, from week to week) or across different people (for example, between healthy people and patients). This is because of the complexity of the signals that are measured by fMRI. In this proposal we will work to improve our understanding of the factors that influence the fMRI signal that we measure, with the intention of being able to make better comparisons between scanning sessions and between different people. We will make measurements and test theories in healthy human volunteers who will undergo MRI scans, and towards the end of the grant period we apply the procedures that we develop to patients with blocked blood supply to the brain. Once this is accomplished the results of this proposal would make fMRI a much better tool for doctors and scientists to use in order to monitor brain diseases, and to develop new treatment methods.

Technical Summary

Functional magnetic resonance imaging (fMRI) is a potentially powerful non-invasive method for measuring brain activity in human subjects via changes in blood oxygenation and flow. The technique has been used widely to study the location of specialized brain processing. However, an impediment to making quantitative assessment of brain activity is the indirect nature of the fMRI response, and its biophysical and physiological complexity. The aim of this work is to address the issues of quantitative comparison, particularly across-session and across-subject effects. Our main goals are: (1) To use MRI methods to estimate normal oxygen-flow coupling in healthy individuals across brain areas and across scanning sessions, and to test the hypothesis that the coupling between oxygen utilisation and blood flow is relatively constant within a brain region across sessions, and to examine variability across cortical regions. (2) Using the knowledge obtained on oxygen-flow coupling within individuals, we wish to understand variations in fMRI sensitivity that is observed across the normal population and to test the hypothesis that the underlying oxygen-flow coupling is relatively constant between healthy individuals, but that other factors, principally CBV-CBF coupling, result in differences in BOLD sensitivity. (3) Finally, we wish to apply these principles to the study of patients with compromised haemodynamic capacity to test the hypothesis that changes in haemodynamic response rather than the underlying neuronal activity may explain a significant proportion of the observed changes in BOLD response over time. Accomplishment of these goals would have significant impact on the ability to study changes in brain function over time, both in normal subjects and in patients. The latter application would have considerable impact on the study of brain disease using fMRI methods, which are currently highly qualitative, and would provide measures of brain metabolism as well as offering methods of comparing populations (e.g. patients versus healthy subjects).

Publications

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Bright MG (2011) The effect of basal vasodilation on hypercapnic and hypocapnic reactivity measured using magnetic resonance imaging. in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

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Bulte D (2007) Measurement of cerebral blood volume in humans using hyperoxic MRI contrast. in Journal of magnetic resonance imaging : JMRI

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Bulte DP (2007) Cerebral perfusion response to hyperoxia. in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

 
Description CRUK/EPSRC Cancer Imaging Centre (named investigator)
Amount £5,000,000 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2008 
End 02/2013
 
Description Centres for Doctoral Training
Amount £3,864,276 (GBP)
Funding ID EP/L016052/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 04/2014 
End 09/2022
 
Description GlaxoSmithKline Studentship
Amount £144,400 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 10/2006 
End 09/2009
 
Description MRC Research Grant
Amount £4,200,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2009 
End 09/2012
 
Description NIHR Oxford Biomedical Research Centre
Amount £127,012 (GBP)
Organisation Oxford University Hospitals NHS Foundation Trust 
Department NIHR Oxford Biomedical Research Centre
Sector Public
Country United Kingdom
Start 03/2009 
End 02/2011
 
Description Wellcome Trust/MRC/DoH etc. Clinical Research Facility (co-PI)
Amount £8,922,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2007 
End 03/2013
 
Title New MRI techniques 
Description We have developed and published a number of novel non-invasive MRI methods for measuring cerebral physiology. These include novel methods of data acquisition optimization; new methods for measurement of cerebral blood flow; new methods for measurement of cerebral blood volume; new methods for measuring blood oxygenation; and new methods for calibrated and quantitative functional MRI. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2007 
Provided To Others? Yes  
Impact These techniques are being translated into clinical practice. A prominent example of this is in Oxford where the techniques will be used in the newly funded Acute Vascular Imaging Centre 
 
Title Novel MRI pulse sequence for CBF measurement 
Description We have developed a new method of human blood flow measurement using MRI that is better tailored to individual measurements, and to making an accurate measurement in pathological situations (e.g. cerebrovascular disease) 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2011 
Provided To Others? Yes  
Impact We plan to use this technique in studying patient populations, and are are about to collaborate with the Juelich Forschungszentrum where they have a combined PET and MRI scanner. They will benefit from our pulse sequence code and we will benefit from access to their PET technology. 
 
Description GlaxoSmithKline collaboration 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution Proposed research collaboration and wrote grant
Collaborator Contribution Access to PET technologies
Impact New MRC grant - G0802179
Start Year 2009
 
Description GlaxoSmithkline 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution Hosted a studentship in collaboration with GSK. Supervised the student.
Impact GSK funded a studentship that interlinked with this grant and helped develop improved methods for acquisition of perfusion imaging data.
Start Year 2006
 
Description Public lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Approx. 50 attendees at a university public outreach event.

Several people asked for further information to be sent to them.
Year(s) Of Engagement Activity 2010
 
Description Several presentations to alumni of University and College 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Several presentations of work at alumni events held across the University and College.

Interest in participation as a human volunteer in the studies, and potential interest in donating money.
Year(s) Of Engagement Activity 2007,2008,2009,2012,2013
 
Description Siemens Healthcare Advisory Committee 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Siemens Healthcare invited PJ to attend an internal strategy meeting of 12 international experts in the field to discuss the future role of arterial spin labelling in their MRI scanners. The ultimate audience was the Product Definition Group of Siemens Healthcare, who determine what products they wish to take forward.

The work that we are doing on real-time feedback ASL was identified by the panel as a top priority for future development so that it could eventually be translated as a clinical product on commercial MRI scanners.
Year(s) Of Engagement Activity 2011,2013
 
Description Talk at local 6th Form College 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Talk to the Year 12 and 13 Science Club at Cherwell School on the principles and applications of Magnetic Resonance Imaging.
Year(s) Of Engagement Activity 2016
 
Description participation in MRC Strategic Workshop on PET Imaging 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Helping construct strategy for PET neuroimaging needs in the UK

Report completed and being acted upon
Year(s) Of Engagement Activity 2008
 
Description regular briefings to newspaper journalists 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Am regularly telephoned and emailed by newspaper science journalists to provide background information and leads relating to imaging developments.

impossible to gauge
Year(s) Of Engagement Activity 2008,2009,2010