Quantitative functional MRI: developing non-invasive neuroimaging to map the human brain's consumption of oxygen

Lead Research Organisation: Cardiff University
Department Name: Sch of Psychology

Abstract

Diseases of the brain including neurological conditions, such as epilepsy, multiple sclerosis and dementia, and common psychiatric conditions such as depression and schizophrenia, have considerable personal, social and economic costs for the sufferers and their carers. Improving the tools at our disposal for quantifying brain function would help with diagnosis, choosing the right treatment for the patient and developing new, more effective, treatments. This proposal aims to develop a reliable non-invasive brain imaging method using magnetic resonance imaging (MRI) that maps, across the whole human brain with a spatial resolution of a few millimetres, the amount of oxygen that the brain is consuming. The rate of oxygen consumption, known as CMRO2, reflects neural activity and can change through disease processes. It provides a marker of disease and treatment related alterations in brain activity. Our proposed method would also map the functional characteristics of brain blood vessels whose health is crucial for the supply of oxygen and nutrients to the brain.

Until recently, it has only been possible to quantitatively map the human brain's metabolic energy use through positron emission tomography (PET), which relies on radioactive tracers. The application of such measurements is limited, as in order to minimise radiation doses, it cannot be applied many times in the same patients or healthy volunteers. This hampers the repeated study of disease or treatment progression and the study of normal brain development and aging. Our proposed method would avoid the use of ionizing radiation, would be cheaper than PET and more widely available, and would expand the applications of quantified CMRO2 mapping to more centres, leading to improved treatment targeting and potential healthcare cost savings.

We have performed some initial tests that show our proposed method to be feasible. It relies on mapping simultaneously the flow of blood to each part of the brain and the oxygenation of the blood leaving each part of the brain. Necessary for the measurement is the modulation of brain blood flow and oxygen levels, achieved by asking volunteers to breathe air enriched with carbon dioxide and oxygen. These procedures involve the volunteer wearing a face-mask but are safe and well tolerated. Our proposed method should yield additional information describing cerebrovascular properties compared to other recently-proposed methods. This means that it would require fewer assumptions which may be not be invalid in the diseased brain, giving our approach a wider scope of application and offering potentially richer clinical information.

This proposal optimises our method to ensure it is efficient and reliable for widespread research and eventually clinical use. We propose a close collaboration between physicists developing the neuroimaging methodology and clinical academic researchers who will help us to demonstrate its clinical feasibility in two common neurological diseases, epilepsy and multiple sclerosis (MS). About 70% of the project will be methodological development to optimise our image acquisition and data analysis strategy to yield accurate and repeatable measurements within about 10 minutes of scanning. The remaining 30% of the project will validate the method in groups of epilepsy and MS patients who volunteer to help us with our research. Validation will be performed by comparison with PET, the current 'gold standard.'

The project will develop and benefit from partnerships with academic and industrial researchers in the UK and internationally. In particular, the work has good potential for application in the drug development industry, a strong industrial sector in the UK, for the development of new and effective compounds to treat psychiatric and neurological disorders. This project would help maintain the UK at the forefront internationally of neuroimaging research, a position it has long held and from which it has benefitted.

Planned Impact

We believe that the research outlined in this proposal would benefit several potential stakeholders outside our immediate academic research arena.

In the short term, basic and clinical neuroscientific researchers would benefit from a non-invasive neuroimaging tool that allows them to address their research questions in humans and animals in a way that radiotracer techniques have previously precluded, for example, through longitudinal studies in healthy volunteers and patients, and in animal studies where there is the opportunity to replace some autoradiographic procedures with imaging and thus reduce the number of animals used in research. The impact in academic research is a necessary step to the longer term and wider health and economic benefits that we would expect success in our project to offer.

The improved, cheaper and thus more widespread capacity in the healthcare sector to map human brain oxygen metabolism is likely to offer benefits to patients and the wider economy. In many cases an MRI-based method to measure cerebral oxygen consumption could replace radiotracer based clinical scans aimed at measuring brain metabolism with oxygen-15 or more commonly radio-labelled glucose (for glucose metabolism), by providing clinically comparable information. Replacement of a proportion of such scans would reduce radiation doses received by patients. However it would open the way to repeated scanning over time and thus the monitoring of disease progression and treatment effectiveness, allowing better and faster decisions to be made about the most effective treatment for the individual patient. Two specific examples, epilepsy and multiple sclerosis (MS), are addressed as 'proof-of-concept' in the present proposal.

As well as replacing some PET scans, metabolic imaging could become available for diagnosis, treatment planning and monitoring a wider range of brain diseases, including epilepsy, MS, head injury, cerebrovascular disease and neurodegenerative conditions such as dementia (e.g. Alzheimer's), as well as psychiatric conditions for which there is a current lack of diagnostic imaging tools. Many of these conditions affect young patients in their economically most active years, causing disability and a reducing their ability to work. Dementia, as well as being debilitating for the patient, imposes a high economic and healthcare burden on society and carers. An improved availability of the clinical tools to diagnose early, stratify patients and select the best treatment early on could reduce the impact of some of these conditions on the individual and on society, as well as reducing the overall health costs through the reduction of accumulated disability. New windows into brain function would also fuel the public's interest in neuroscience and create an educational impact across all age groups.

The improved understanding of cerebral metabolism offered by the provision of a tool to study it more widely may be expected to lead to hypotheses for testing new targeted rehabilitative interventions and drug therapies for the treatment of neurological and psychiatric conditions. Apart from the long-term health benefits this would be of great economic value to the drug discovery and development industry, an area of the world's knowledge-economy in which the UK is particularly strong. The success of our methods could make a considerable contribution to evaluating new compounds in the pharmaceutical industry. The development process for new treatments is an extremely expensive business particularly because of the cost of the high failure rate during late-stage clinical trials. Better imaging tools to provide biomarkers of drug action in small cohorts of subjects would help the industry predict better which compounds are likely to fail. Prof Wise has 12 years' experience in developing fMRI methods in concert with large pharmaceutical companies in the UK and internationally.

Publications

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Champagne AA (2020) Changes in volumetric and metabolic parameters relate to differences in exposure to sub-concussive head impacts. in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

 
Description We have made significant advances in the modelling of combined BOLD and CBF signals to estimate OEF and CMRO2. We have developed a model with improved accuracy and a forward modelling based approach for the estimation of these key physiological parameters from experimental data.
Exploitation Route We are now testing our new methods in the clinical area to test their utlity in neurological and psychiatric conditions.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description An integrated MRI tool to map brain microvascular and metabolic function: improving imaging diagnostics for human brain disease
Amount £1,116,430 (GBP)
Funding ID EP/S025901/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 10/2019 
End 03/2023
 
Description MRC Confidence in Concept (Cardiff University)
Amount £49,884 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2017 
End 04/2018
 
Description MRC Project Grant
Amount £1,865,362 (GBP)
Funding ID MR/N01233X/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2016 
End 04/2020
 
Description Project grant for network creation
Amount £249,807 (GBP)
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2016 
End 09/2019
 
Description Wellcome ISSF
Amount £49,436 (GBP)
Organisation Cardiff University 
Sector Academic/University
Country United Kingdom
Start 01/2013 
End 06/2015
 
Description Wellcome Trust Strategic Award
Amount £4,900,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2016 
End 06/2021
 
Title dual-calibrated fMRI 
Description This is a MRI scanning protocol (dual-excitation BOLD and CBF ASL acquisition) combined with forward modelling of the joint data to estimate brain oxygen extraction fraction, blood flow, rate of cerebral metabolic oxygen consumption, vascular reactivity and blood volume. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2013 
Provided To Others? Yes  
Impact It is now being applied in clinical reserch studies in CUBRIC and in pharmacological interventions. 
 
Description Bulk measurement of cerebral venous oxygenation 
Organisation University of Pennsylvania
Country United States 
Sector Academic/University 
PI Contribution MRI expertise to test new oxygen sensitive sequences
Collaborator Contribution Binary sequences for MRI scanners and analysis software.
Impact no outputs yet
Start Year 2016
 
Description Caffeine effects on brain function 
Organisation University of Bristol
Department School of Experimental Psychology
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of neuroimaging expertise (EEG-FMRI) to study anxiety effects of caffeine. Neurovascular coupling alterations induced by caffeine.
Collaborator Contribution Intellectual contribution in evaluating neurocognitive effects of caffeine in low caffeine consumers.
Impact 2 preliminary grant applications made to the BBSRC (unsuccessful). One abstract accepted in 2011 and another in submission. Neuroimage article published.
Start Year 2008
 
Description Cardiff Anaesthetic and Intensive Care Medicine 
Organisation Cardiff University
Department Department of Anaesthetics, Intensive Care and Pain Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Neuroimaging (EEG-FMRI, MEG) expertise for studying anaesthetic action.
Collaborator Contribution Intellectual contribution in anaesthetic research. Provision of practical anaesthetic research (drug delivery and patient care).
Impact Successful grant applications. International conference presentations. Manuscripts in submission. This is multidisciplinary involving physicists and anaesthetists.
Start Year 2008
 
Description Cereborvascular physiological modelling 
Organisation McGill University
Country Canada 
Sector Academic/University 
PI Contribution MRI data and neurophysiology expertise
Collaborator Contribution Data modelling expertise.
Impact Publications
Start Year 2014
 
Description High-resolution cerebrovascular imaging at UHF 
Organisation Leiden University Medical Center
Country Netherlands 
Sector Academic/University 
PI Contribution MRI and physiological expertise
Collaborator Contribution Access to 7T MRI and MRI expertise for vessel imaging
Impact Pulications
Start Year 2015
 
Description Quantitative FMRI 
Organisation University of California, San Diego (UCSD)
Department Center for Functional MRI
Country United States 
Sector Academic/University 
PI Contribution Expertise on physiological challenges performed in the MRI scanner.
Collaborator Contribution Software for controlling MRI scanner to make quantitative measurements of cerebral blood flow and oxygen consumption.
Impact Manuscripts in preparation. Successful fellowship applications from Wellcome Trust.
Start Year 2006
 
Description Santa Lucia Foundation, Rome 
Organisation Fondazione Santa Lucia
Country Italy 
Sector Charity/Non Profit 
PI Contribution Expertise in supervising a post-doc in Rome
Collaborator Contribution Funding a post-doc to do clinical research in Rome
Impact Gili T, Saxena N, Diukova A, Murphy K, Hall JE, Wise RG. The thalamus and brainstem act as key hubs in alterations of human brain network connectivity induced by mild propofol sedation. Journal of Neuroscience. 2013 Feb 27;33(9):4024-31. doi: 10.1523/JNEUROSCI.3480-12.2013. PMID:23447611 Saxena N, Muthukumaraswamy SD, Diukova A, Singh K, Hall J, Wise R. Enhanced stimulus-induced gamma activity in humans during propofol-induced sedation. PLoS One. 2013;8(3):e57685. doi: 10.1371/journal.pone.0057685. Epub 2013 Mar 6. PubMed PMID: 23483920; PubMed Central PMCID: PMC3590225.
Start Year 2010