Biophysical modelling of white matter structure

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

Abstract

Brain white matter makes up the wires that connect different regions in the brain. It is affected in hundreds of brain diseases, and is the main target of many of these. It is important to be able to make detailed measurements of features of white matter if we are trying to understand the nature of a disease; if we want to watch the progression of a disease in a particular patient; or if we want to find out if a drug is being effective against the disease. At the moment, it is only possible to take these detailed measurements in a dead brain using a microscope. We can take measurements in living people using an MRI machine, but these are much coarser, only giving us a rough estimate that something about the white matter has changed. We propose to use different kinds of MRI data together with mathematical modelling techniques to make detailed measurements of specific features of white matter, such as the cell size, the density of the cells and the amount of electrical insulation. The ability to take these measurements in-vivo will give doctors and clinical researchers access to a great deal more information when they are suggesting treatment, or researching into the disease.

Technical Summary

We aim to use diffusion MRI and T2-relaxometry data to infer cellular features (axon density, axon radius, and myelin content) along white matter pathways in the in-vivo brain. Although in-part measurable from ex-vivo diffusion MR data, such measurements have, to-date, required image acquisition protocols that are not possible in-vivo. We intend to address these problems using two strategies. First, we will combine two types of MR data that contain complementary information about these key parameters. This will help to resolve ambiguity about key biophysical parameters, such as myelination content and axon density, that exists when using diffusion data alone. Second, we will combine data across imaging voxels that lie within the same white matter pathways ? this will help to overcome the signal-to-noise limitations of in-vivo imaging data. In both cases we will use Bayesian strategies to combine data. We will build a biophysical model of white matter structure capable of predicting diffusion and relaxometry from a given set of parameters, and use both types of data symmetrically to invert the model. We will then place this model at the heart of a Bayesian global tractography approach that we have previously developed. We will extend this global approach to include a spatial model on the key biophysical parameters of interest to enforce only smooth, or no, change along a white matter pathway. This approach will have two important effects. First, it will essentially pool information across voxels in the same white matter pathway. This will reduce our SNR requirements for estimating key parameters. Second, it will automatically and seamlessly incorporate the biophysical information into the tractography routine that estimates the white matter pathways. This is potentially a significant step for tractography. Typically, tractography relies on orientation of diffusion within each voxel. In many cases there are ambiguities between neighbouring pathways that cause false positive and false negative connections from tractography. For example, it is not possible to distinguish two crossing fibres from two ?kissing? fibres with conventional tractography. Although biophysical parameters are expected to change slowly along a white matter pathway, they may vary to a greater extent between neighbouring pathways. The biophysical information will therefore inform the tractography routine in situations where the orientational information is ambiguous. Biophysical parameters inferred from our model will be validated against classical histological techniques in ex-vivo samples.

Publications

10 25 50
 
Description CONNECT Consortium Of Neuroimagers for the Non-invasive Exploration of Brain Connectivity and Tracts (3m euros across 9 participants)
Amount £140,000 (GBP)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start  
 
Description Centre grant to establish Wellcome Centre for Integrative Neuroimaging (Behrens, Co-I)
Amount £11,463,085 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2017 
End 04/2022
 
Description HUMAN CONNECTOME PROJECT ($30m across 9 centres)
Amount £2,100,000 (GBP)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start  
 
Description LIFESPAN HUMAN CONNECTOME PROJECT in DEVELOPMENT and AGING ($2x14m across 9 centres)
Amount $1,000,000 (USD)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 05/2016 
End 05/2020
 
Description MRC Research Grant (Biophysical models of white matter)
Amount £350,000 (GBP)
Funding ID G0800578 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description Mechanisms of behavioural control (Behrens)
Amount $600,000 (USD)
Organisation James S. McDonnell Foundation 
Sector Charity/Non Profit
Country United States
Start 10/2013 
End 09/2019
 
Description Senior Research Fellowship - Neural mechanisms of behavioural control (Behrens)
Amount £1,968,459 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2015 
End 09/2019
 
Description Strategic award (Behrens, Co-I)
Amount £2,000,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2012 
End 08/2018
 
Description Wellcome Trust Research Career Development Fellowship (Biophysical mechanisms of goal-based decision-making)
Amount £736,658 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Title Cross subject diffusion software 
Description Software for analyzing diffusion-weighted brain images. 
Type Of Material Data analysis technique 
Year Produced 2009 
Provided To Others? Yes  
Impact This tool is used by other researchers, including collaborators and non-collaborators working in the field. 
 
Description Human Connectome Project 
Organisation Washington University in St Louis
Department Department of Neuroscience
Country United States 
Sector Academic/University 
PI Contribution Our team is the backbone of methods development for this vast project. We develop software tools that will be used to study brain connections in a large cohort of subjects with unprecedented data quality
Collaborator Contribution Provide state of the art data Provide expertise in brain anatomy
Impact Publication 21908183, 27071694, 27571196, 26260428, 23702418, 23668970. Software release of the HCP pipelines: https://github.com/Washington-University/Pipelines. Development of state of the art approach for correcting distortions in neuroimaging data. Publications: 26481672, 27393418 Software release of relevant toolbox: https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/eddy
Start Year 2010
 
Description MGH 
Organisation Massachusetts General Hospital
Department Martinos Center for Biomedical Imaging Massachusetts
Country United States 
Sector Academic/University 
PI Contribution We have pioneered a method for tracking brain connections, which our collaborators improved upon
Collaborator Contribution Improvement on our software tool
Impact Publication (22016733) Software tool
Start Year 2008
 
Description New MRI Sequences 
Organisation Global Medical Excellence Cluster (GMEC)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Our experience in mathematical modelling was essential for the implementation and optimisation of new MRI sequences
Collaborator Contribution Development of new MRI sequences to probe microstructure
Impact Journal publications (NeuroImage 22008372 and 21473920) Shared PhD student between Dr Karla Miller and Dr Saad Jbabdi working on sequence development
Start Year 2009
 
Description Primate functional anatomy 
Organisation Global Medical Excellence Cluster (GMEC)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Our expertise in diffusion imaging was key to the data analyses, where we were able to apply state of the art methods to ask questions about primate neuro-anatomy, function, and comparisons with humans.
Collaborator Contribution Provided primate neuro-imaging data and expertise in primate neuro-anatomy
Impact Journal publications (1 Science [22053054], 1 Journal of Neuroscience [21411650], 1 Cerebral Cortex [21955921]) Implementation of software tools to analyse primate brain data in a similar manner to human data
Start Year 2008
 
Description White matter anatomy of the macaque brain 
Organisation University of Rochester
Department University of Rochester Medical Centre
Country United States 
Sector Academic/University 
PI Contribution Ongoing collaboration to validate white matter anatomy inferred by imaging in macaques with chemical tracing. My expertise in tractography is a central part of this collaboration
Collaborator Contribution Provide ground-truth mappings of white matter tracts using tracers
Impact Publications 23407972 and 23283687
Start Year 2012
 
Description New Scientist 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Wrote an artiocle for the new scientist about diffusion tractography

Public learnt about neuroscience
Year(s) Of Engagement Activity 2010
 
Description Radio program 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Went on Radio 4 program "All in the Mind" to describe diffusion tractography

Publich learnt about Neuroscience
Year(s) Of Engagement Activity 2011