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.
Organisations
Publications

Bach DR
(2011)
Deep and superficial amygdala nuclei projections revealed in vivo by probabilistic tractography.
in The Journal of neuroscience : the official journal of the Society for Neuroscience

Behrens TE
(2012)
Human connectomics.
in Current opinion in neurobiology

Blumensath T
(2013)
Spatially constrained hierarchical parcellation of the brain with resting-state fMRI.
in NeuroImage

Bosnell RA
(2011)
Motor practice promotes increased activity in brain regions structurally disconnected after subcortical stroke.
in Neurorehabilitation and neural repair

Cerliani L
(2012)
Probabilistic tractography recovers a rostrocaudal trajectory of connectivity variability in the human insular cortex.
in Human brain mapping

Craddock RC
(2013)
Imaging human connectomes at the macroscale.
in Nature methods

Crofts JJ
(2011)
Network analysis detects changes in the contralesional hemisphere following stroke.
in NeuroImage


Douaud G
(2009)
In vivo evidence for the selective subcortical degeneration in Huntington's disease.
in NeuroImage

Eickhoff SB
(2010)
Anatomical and functional connectivity of cytoarchitectonic areas within the human parietal operculum.
in The Journal of neuroscience : the official journal of the Society for Neuroscience
Description | CONNECT Consortium Of Neuroimagers for the Non-invasive Exploration of Brain Connectivity and Tracts (3m euros across 9 participants) |
Amount | £140,000 (GBP) |
Funding ID | 238292 |
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 | 03/2017 |
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 | 04/2016 |
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 | Public |
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 | 09/2013 |
End | 09/2019 |
Description | Principal Research Fellowship |
Amount | £2,844,723 (GBP) |
Funding ID | 219525/Z/19/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2020 |
End | 02/2025 |
Description | Senior Research Fellowship - Neural mechanisms of behavioural control (Behrens) |
Amount | £1,968,459 (GBP) |
Funding ID | 104765/Z/14/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2015 |
End | 09/2019 |
Description | Strategic award (Behrens, Co-I) |
Amount | £2,000,000 (GBP) |
Funding ID | 098369/Z/12/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2012 |
End | 08/2018 |
Description | Wellcome Trust Collaborative Award |
Amount | £2,276,345 (GBP) |
Funding ID | 214314/Z/18/Z |
Organisation | University of Oxford |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2019 |
End | 02/2024 |
Description | Wellcome Trust Research Career Development Fellowship (Biophysical mechanisms of goal-based decision-making) |
Amount | £736,658 (GBP) |
Funding ID | 088312 |
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 | Model of mechanisms or symptoms - human |
Year Produced | 2009 |
Provided To Others? | Yes |
Impact | This tool is used by other researchers, including collaborators and non-collaborators working in the field. |
URL | http://fsl.fmrib.ox.ac.uk |
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 | Hospitals |
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 |