An integrated MRI tool to map brain microvascular and metabolic function: improving imaging diagnostics for human brain disease

Lead Research Organisation: CARDIFF UNIVERSITY
Department Name: Sch of Psychology

Abstract

Brain diseases such as tumours, head injury, epilepsy, multiple sclerosis and dementias have considerable personal, social and economic costs for the sufferers and their carers. While magnetic resonance imaging (MRI) has revolutionised the management of many brain conditions in the last 40 years, there is a need for better tools for quantifying the brain's supply of energy in terms of blood flow and vascular function and it use of energy in terms of metabolic function. For example, in the case of the most common forms of brain tumour, glioma, we lack detailed information about the heterogeneity of tissue function that could help guide better treatments such as more targeted and individualised combined radiotherapy and drug programmes. Understanding more about the tumour microenvironment will also promote the development of more effective treatments. For high-grade gliomas, particularly glioblastoma, the prognosis remains poor, highlighting an urgent clinical need.

Recently, we at Cardiff University Brain Research Imaging Centre (CUBRIC), and others, have developed MRI-based tools (termed dual calibrated fMRI) to map across the human brain, with a spatial resolution of a few millimetres, the amount of oxygen that the brain is consuming (known as CMRO2) along with measures of the efficiency of blood supply. CMRO2 reflects neural activity and can be altered with disease such as tumour where there is cell proliferation and energy metabolism is changed. Knowing also the functional properties of brain blood vessels and the oxygen status of brain tissue is important for understanding whether blood supply is sufficient or the vasculature is abnormal as is often seen in tumours where vessels proliferate. Our newly developed methods have shown promise in revealing abnormalities of brain tissue energy consumption in multiple sclerosis and epilepsy. In epilepsy they may offer an alternative to the use of radiation-based PET scans in the evaluation of patients for brain surgery by identifying areas in the brain with abnormally low metabolism.

However, to produce a wider clinical impact it is necessary to advance the MRI and data analysis further, such that they could then be taken forward for commercial development and routine clinical use, initially within clinical trials. Two-thirds of the proposed project will address engineering and physical science challenges to (i) speed up data acquisition to about 10 mins, a clinically feasible time, by optimising the MRI data acquisition and analysis, (ii) widen the range of tissue pathology that we can reliably measure through collection of additional MRI information and detailed biophysical modelling of tissue properties and (iii) implement efficient artificial intelligence (neural network) based data analysis that can rapidly feed the images to the clinician at the MRI scanner. The remaining one-third of the project will demonstrate the feasibility of the method and its value in application to brain tumour (glioma). We aim to show that we can map the heterogeneity of tumour tissue that can reveal the type of tumour, where it is actively growing, where it is and is not responding to treatment and where radiotherapy may be damaging healthy tissue, all helping to guide treatment decisions for maximum efficacy.

Central to the success of our proposal are our partnerships with industry and the NHS. Siemens will contribute the expertise of its onsite scientist at CUBRIC for the development of the MRI technology. The Velindre Cancer Centre, South Wales' principal centre for oncology, will partner on the clinical pilot studies and help to evaluate imaging for future patient benefit. Our partners will help us to bring the methods to the point within this project, if successful, of commercial development for healthcare benefit and larger scale clinical trials to demonstrate how the methods may be used in clinical practice for diagnosis, treatment planning and monitoring.

Planned Impact

The research proposed would ultimately benefit patients with common neurological diseases as well as patients with brain tumours. Cancer Research UK has identified brain tumours as one of its four cancers of unmet need because of their poor outcome. In the short term, researchers would benefit from a non-invasive neuroimaging tool that allows them to map brain energy supply and oxygen consumption with good reliably across a wide range of tissue pathology. Tissue hypoxia is a well-recognised cause of treatment resistance, particularly to radiotherapy. Identifying areas of hypoxia within tumours at baseline, or evolving areas of hypoxia during treatment, could allow radiotherapy treatment plans to be personalised or adapted mid-treatment based on tumour response. It would therefore promote research into radiotherapy personalisation. This work addresses an important priority area for Neuro-Oncology research identified by the James Lind Alliance in 2015 including improving techniques for subtyping brain tumours for treatment selection. Specifically, this project is supporting efforts to improve the outcome of patients with brain cancers through better tumour control and survival, reduced side effects and quicker recovery from treatment with improved quality of life.

As well as the contribution to improved treatment for brain cancer, for which urgent improvements are needed, metabolic brain imaging could become widespread for diagnosis, treatment planning and monitoring a wide 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. The ability to map human brain oxygen metabolism and detailed cerebrovascular (including microvascular) function could offer benefits to many of these patients. In some cases, the MRI-based methods may replace radiotracer based clinical scans aimed at measuring brain metabolism, by providing clinically comparable information (we have already collected some evidence for the feasibility of this in epilepsy). Use of MRI in some of these conditions could expand the patient groups that benefit from metabolic imaging and open the way to repeated scanning over time and thus the monitoring of disease progression and treatment effectiveness, allowing more individualised treatment pathways.

Some of these brain conditions affect young patients in their economically most active years, causing disability and a reducing their ability to work. Dementia, however, 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.

Commercialisation of a new clinical imaging product, incorporating both imaging and analysis technology developments, would provide a positive economic impact for imaging technology providers such as Siemens, other MRI vendors and potential developers of image analysis and interpretation tools based on artificial intelligence techniques. The new imaging tools would be valuable in drug development (we have already shown proof-of-concept in a pilot pharmacological study of caffeine's effects on the brain). The pharmaceutical industry needs tools to demonstrate brain penetration of new compounds and early signals of efficacy to de-risk the very expensive drug development pipeline. The UK would benefit greatly given its strength in drug discovery and development. Prof Wise has 18 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

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Chandler HL (2023) Reduced brain oxygen metabolism in patients with multiple sclerosis: Evidence from dual-calibrated functional MRI. in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

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Chiarelli AM (2022) A flow-diffusion model of oxygen transport for quantitative mapping of cerebral metabolic rate of oxygen (CMRO2) with single gas calibrated fMRI. in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

 
Description Head Impact Research cited in Systematic Review
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in systematic reviews
 
Description Sir Henry Dale Fellowship, "Mapping the energetic pathways of the brain: Ultra-high-field MRI of cerebral oxygen and glucose utilisation"
Amount £1,551,810 (GBP)
Funding ID 220575/Z/20/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2021 
End 12/2025
 
Title Flow-diffusion constrained mapping of cerebral oxygen metabolism with MRI 
Description I have developed a new method for mapping brain oxygen metabolism with MRI. The method combines flow-diffusion modelling of oxygen transport with biophysical models of oxygen realted MRI signals. The new method greatly simplifies existing methods that rely on multiple respiratory gas challenges during MRI scanning. 
Type Of Material Data analysis technique 
Year Produced 2022 
Provided To Others? Yes  
Impact The new method removes the need for repiratory gas modulation for human MRI subjects. Thus, making the method significantly more tolerable for particpants and much easier to acquire data. This has led to the initiatiion of collaborative reseach projects for scanning in clinical populations 
URL https://journals.sagepub.com/doi/pdf/10.1177/0271678X221077332
 
Description Deep learning paradigm agnostic method for parametric mapping with physiological MRI 
Organisation Concordia University
Country Canada 
Sector Academic/University 
PI Contribution Leadership in the development of deep learning method for parametric mapping from physiological MRI data
Collaborator Contribution PhD student time decicated to method development
Impact New collaboration no outputs yet
Start Year 2023
 
Description ITAB - imaging tissue physiology in primary brain tumours 
Organisation University of Chieti-Pescara
Department Department of Neuroscience and Imaging
Country Italy 
Sector Academic/University 
PI Contribution MRI sequence development and data analysis
Collaborator Contribution Physiological modelling
Impact Germuska M, Chandler H, Okell T, Fasano F, Tomassini V, Murphy K, Wise R. A frequency-domain machine learning method for dual-calibrated fMRI mapping of oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen consumption (CMRO2). Front Artif Intell. 2020 Mar 31;3:12. doi: 10.3389/frai.2020.00012. PMID: 32885165; PMCID: PMC7116003.
Start Year 2019
 
Description Juelich - multicontrast tumour imaging 
Organisation Julich Research Centre
Country Germany 
Sector Academic/University 
PI Contribution Physiological modelling and patient data
Collaborator Contribution MRI sequences
Impact none
Start Year 2020
 
Description Robust MRI imaging of brain oxygen metabolism 
Organisation Max Planck Society
Department Max Plank Institute for Human Cognitive and Brain Sciences
Country Germany 
Sector Academic/University 
PI Contribution Physiological modelling, MRI sequence programming, and data analysis for the development of robust methods to measure brain oxygen metabolism and oxygen diffusivity with MRI
Collaborator Contribution MRI sequence programming for arterial spin labelling and phsyiological modelling
Impact 1. Dual-calibrated fMRI measurement of absolute cerebral metabolic rate of oxygen consumption and effective oxygen diffusivity. Neuroimage. 2019 Jan 1; 184: 717-728. 2. A Frequency-Domain Machine Learning Method for Dual-Calibrated fMRI Mapping of Oxygen Extraction Fraction (OEF) and Cerebral Metabolic Rate of Oxygen Consumption (CMRO2). Front Artif Intell. 2020 Mar 31;3:12. 3. Assessing the repeatability of absolute CMRO2, OEF and haemodynamic measurements from calibrated fMRI. Neuroimage. 2018 Jun; 173: 113-126.
Start Year 2016
 
Description Robust MRI imaging of brain oxygen metabolism 
Organisation Siemens Healthcare
Department Siemens Healthcare Ltd
Country United Kingdom 
Sector Private 
PI Contribution Physiological modelling, MRI sequence programming, and data analysis for the development of robust methods to measure brain oxygen metabolism and oxygen diffusivity with MRI
Collaborator Contribution MRI sequence programming for arterial spin labelling and phsyiological modelling
Impact 1. Dual-calibrated fMRI measurement of absolute cerebral metabolic rate of oxygen consumption and effective oxygen diffusivity. Neuroimage. 2019 Jan 1; 184: 717-728. 2. A Frequency-Domain Machine Learning Method for Dual-Calibrated fMRI Mapping of Oxygen Extraction Fraction (OEF) and Cerebral Metabolic Rate of Oxygen Consumption (CMRO2). Front Artif Intell. 2020 Mar 31;3:12. 3. Assessing the repeatability of absolute CMRO2, OEF and haemodynamic measurements from calibrated fMRI. Neuroimage. 2018 Jun; 173: 113-126.
Start Year 2016
 
Description Robust MRI imaging of brain oxygen metabolism 
Organisation Wellcome Centre for Integrative Neuroimaging
Country United Kingdom 
Sector Public 
PI Contribution Physiological modelling, MRI sequence programming, and data analysis for the development of robust methods to measure brain oxygen metabolism and oxygen diffusivity with MRI
Collaborator Contribution MRI sequence programming for arterial spin labelling and phsyiological modelling
Impact 1. Dual-calibrated fMRI measurement of absolute cerebral metabolic rate of oxygen consumption and effective oxygen diffusivity. Neuroimage. 2019 Jan 1; 184: 717-728. 2. A Frequency-Domain Machine Learning Method for Dual-Calibrated fMRI Mapping of Oxygen Extraction Fraction (OEF) and Cerebral Metabolic Rate of Oxygen Consumption (CMRO2). Front Artif Intell. 2020 Mar 31;3:12. 3. Assessing the repeatability of absolute CMRO2, OEF and haemodynamic measurements from calibrated fMRI. Neuroimage. 2018 Jun; 173: 113-126.
Start Year 2016
 
Description Streamlined approach to measuring brain physiology with calibrated fMRI 
Organisation Northwestern University
Country United States 
Sector Academic/University 
PI Contribution Physiological modelling, data acquisition and analysis,
Collaborator Contribution MRI sequence programming, statistical analysis, physiological modelling
Impact 1. J Cereb Blood Flow Metab. 2022 Jul;42(7):1192-1209. A flow-diffusion model of oxygen transport for quantitative mapping of cerebral metabolic rate of oxygen (CMRO2) with single gas calibrated fMRI. 2. https://doi.org/10.1177/0271678X221121849. Reduced brain oxygen metabolism in patients with multiple sclerosis: Evidence from dual-calibrated functional MRI
Start Year 2018
 
Description Streamlined approach to measuring brain physiology with calibrated fMRI 
Organisation University of Bath
Department Department of Psychology
Country United Kingdom 
Sector Academic/University 
PI Contribution Physiological modelling, data acquisition and analysis,
Collaborator Contribution MRI sequence programming, statistical analysis, physiological modelling
Impact 1. J Cereb Blood Flow Metab. 2022 Jul;42(7):1192-1209. A flow-diffusion model of oxygen transport for quantitative mapping of cerebral metabolic rate of oxygen (CMRO2) with single gas calibrated fMRI. 2. https://doi.org/10.1177/0271678X221121849. Reduced brain oxygen metabolism in patients with multiple sclerosis: Evidence from dual-calibrated functional MRI
Start Year 2018
 
Description Streamlined approach to measuring brain physiology with calibrated fMRI 
Organisation University of California - San Diego School of Medicine
Country United States 
Sector Academic/University 
PI Contribution Physiological modelling, data acquisition and analysis,
Collaborator Contribution MRI sequence programming, statistical analysis, physiological modelling
Impact 1. J Cereb Blood Flow Metab. 2022 Jul;42(7):1192-1209. A flow-diffusion model of oxygen transport for quantitative mapping of cerebral metabolic rate of oxygen (CMRO2) with single gas calibrated fMRI. 2. https://doi.org/10.1177/0271678X221121849. Reduced brain oxygen metabolism in patients with multiple sclerosis: Evidence from dual-calibrated functional MRI
Start Year 2018
 
Description Streamlined approach to measuring brain physiology with calibrated fMRI 
Organisation University of Chieti-Pescara
Country Italy 
Sector Academic/University 
PI Contribution Physiological modelling, data acquisition and analysis,
Collaborator Contribution MRI sequence programming, statistical analysis, physiological modelling
Impact 1. J Cereb Blood Flow Metab. 2022 Jul;42(7):1192-1209. A flow-diffusion model of oxygen transport for quantitative mapping of cerebral metabolic rate of oxygen (CMRO2) with single gas calibrated fMRI. 2. https://doi.org/10.1177/0271678X221121849. Reduced brain oxygen metabolism in patients with multiple sclerosis: Evidence from dual-calibrated functional MRI
Start Year 2018
 
Description Streamlined approach to measuring brain physiology with calibrated fMRI 
Organisation University of Pennsylvania
Country United States 
Sector Academic/University 
PI Contribution Physiological modelling, data acquisition and analysis,
Collaborator Contribution MRI sequence programming, statistical analysis, physiological modelling
Impact 1. J Cereb Blood Flow Metab. 2022 Jul;42(7):1192-1209. A flow-diffusion model of oxygen transport for quantitative mapping of cerebral metabolic rate of oxygen (CMRO2) with single gas calibrated fMRI. 2. https://doi.org/10.1177/0271678X221121849. Reduced brain oxygen metabolism in patients with multiple sclerosis: Evidence from dual-calibrated functional MRI
Start Year 2018
 
Description In2scienceUK host 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact I hosted 2 A-level students (from disadvantaged backgrounds) for a week within the lab. The aim of the placement was to nuture an interest in science and research and provide support for pupils that may have been missin gthis as part of their regular education.
Year(s) Of Engagement Activity 2023
URL https://in2scienceuk.org/
 
Description Participation in open days for the School of Physics and Astronomy, Cardiff University 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Presentation related to my research in the context of prospective undergraduates open days at the School of Physics and Astronomy (Cardiff University)
Year(s) Of Engagement Activity 2021,2022,2023
 
Description Public Webinar Series on Imaging Cerebral Physiology 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact A monthly webinar series to foster exchange of ideas and highlight exciting research in the field of Imaging Cerebral Physiology. The webinars give a platform for early career researchers to engage internationally, highlight their work, ask questions from experts in the field, and forge new link for future research. All webinars are recorded and available to the public on YouTube. The general public also appear to engage with the content, with the most viewed webinar so far has over 4,000 views on YouTube.
Year(s) Of Engagement Activity 2021,2022,2023
URL https://www.youtube.com/@imagingcerebralphysiologyn7583/videos