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The Developing Human Connectome
David Edwards DSc, F Med Sci
November 2, 2014 1
DevelopingHumanConnectomeProject
David Edwards
Jo Hajnal
Stephen Smith
Daniel Rueckert
DevelopingHumanConnectomeProject
I have no disclosures to make
DevelopingHumanConnectomeProject
Human Connectome Projects
• A comprehensive mapping of neural connections and their variation
– 87 billion neural cells
– Uncounted synapses
• Mapped at different scales
– Micro (micron)
– Macro (millimetre)
• Structure and Function DevelopingHumanConnectomeProject
A connectome of a single subject from the Human Connectome Project(~1 TB)
THE BLUE BRAINPROJECT
DevelopingHumanConnectomeProject
Connectomics over scale
Micro-connectomes:• Reconstruct all synapses, axons, dendrites• ~1 mm scale• Aim for high fidelity• Animal models (e.g., mouse)• Excludes long-distance pathways
Knott et al. (J. Neurosci., 2008)
Macro-connectomes:• Reconstruct long-distance pathways• Humans, in vivo neuroimaging• Spatial resolution: ~1 - 2 mm voxels• Tolerate errors, uncertainties• Analyze individual variability
Behrens & Glasser (unpublished)
Courtesy: David Van Essen
DevelopingHumanConnectomeProject
DevelopingHumanConnectomeProject
Structural connections: the wiring diagram of the brain
• White matter tracts carry information
• Visualised in live humans using diffusion Magnetic Resonance Imaging (dMRI)
DevelopingHumanConnectomeProject
DevelopingHumanConnectomeProjectFunctional connections:
coordinated activation
• Brain structures activate together when engaged in a task
• Functional connections mapped by functional connectivity Magnetic Resonance Imaging (fcMRI)
Adult fcMRI images courtesy of Marcus Raichle
The Developing Human Connectome
David Edwards DSc, F Med Sci
November 2, 2014 2
DevelopingHumanConnectomeProjectHuman Connectomics
Years
AdulthoodBirth Puberty
Conception
Comprehensive mapping of normal adult brain$30 million, 5 year projectUS consortium + Smith Group
weeks
DevelopingHumanConnectomeProjectOpportunities and challenges
• Advantages of developmental data
– Biologically important period
– Assembly of connections is dominant event
– Big differences over age and between subject groups
– Long-term follow-up to adulthood for life-course study
• Special challenges
– Subjects are small, vulnerable and moving
– Imaging in utero
– 4-D datasets with massive change 20
Connections
40weeks
(Kapellou et al, 2006)(Takahashi et al, 2012 (post mortem data))
Brain size
DevelopingHumanConnectomeProjectTractography
DevelopingHumanConnectomeProject
DevelopingHumanConnectomeProject
DevelopingHumanConnectomeProject
White matter tracts in a newborn infant
DevelopingHumanConnectomeProject
DevelopingHumanConnectomeProject
4-Dimensional brain atlas
Kulisova-Murgusova et al.Neuroimage 2011 54(4):2750-63
Serag et al Neuroimage2012 59(3):2255-65
The Developing Human Connectome
David Edwards DSc, F Med Sci
November 2, 2014 3
DevelopingHumanConnectomeProject
a b c
d
Orthogonal planes (a-c) and volume rendering (d) ofa T1-weighted MR image of a 2-year-old brain. Anautomatically created atlas is overlaid on theimages, following non-rigid registration of a cohort ofadult datasets on the 2-year-old brain, labelpropagation and fusion of the transformed andindividualised adult atlases. This technique allowsrapid, objective quantification of brain development
(Gousias et al Neuroimage 2010)
DevelopingHumanConnectomeProjectA Brain Connectome:
Interconnectivity between 83 brain regions
Robinson et al, MICCAI 2008;11(Pt 1):486-93; NeuroImage 2010, 50: 910-18
DevelopingHumanConnectomeProject
DevelopingHumanConnectomeProjectStructural connections:
preliminary data
• Coarse connectome
– Environmental influences
• Voxel level
– Rich club organisation
– Thalamocortical Connectivity
• Intra-cortical connectivity
DevelopingHumanConnectomeProject
DevelopingHumanConnectomeProjectInitial sparse, coarse, consensus
connectome for infants born preterm
Pandit et al, Cerebral Cortex 2013
DevelopingHumanConnectomeProject
DevelopingHumanConnectomeProject
Rich club organization.
Collin G et al. Cereb. Cortex 2013;cercor.bht064
© The Author 2013. Published by Oxford University Press.
Pandit et al, Cerebral Cortex 2013
DevelopingHumanConnectomeProject
DevelopingHumanConnectomeProjectEffect of growth and preterm birth on
connectivity
Pandit et al, Cerebral Cortex 2013
DevelopingHumanConnectomeProject
The Developing Human Connectome
David Edwards DSc, F Med Sci
November 2, 2014 4
DevelopingHumanConnectomeProject
Connections growing most strongly
DevelopingHumanConnectomeProject
DevelopingHumanConnectomeProjectEffect of growth and preterm birth on
connectivity
DevelopingHumanConnectomeProject
DevelopingHumanConnectomeProject
Node size
smaller cortical nodes
DevelopingHumanConnectomeProject
DevelopingHumanConnectomeProject
500 randomly distributed regions of ~equal size (250 per hemisphere)
Repartition And Repeat
Tractography
Iterated random samplingDevelopingHumanConnectomeProject
DevelopingHumanConnectomeProject
Group data: Rich Club features
Rich Club Coefficient
Normalised Rich Club Coefficient
DevelopingHumanConnectomeProject
Rich Club:40 weeks gestation
DevelopingHumanConnectomeProject
Ball et al, Proc Nat Acad Sci USA 2014
The Developing Human Connectome
David Edwards DSc, F Med Sci
November 2, 2014 5
DevelopingHumanConnectomeProject
Rich Club 30 weeks gestation
DevelopingHumanConnectomeProject
Ball et al, Proc Nat Acad Sci USA 2014
DevelopingHumanConnectomeProject
DevelopingHumanConnectomeProject
Changes 30 to 40 weeks
Ball et al, Proc Nat Acad Sci USA 2014
DevelopingHumanConnectomeProject
Euclidian lengths of connections
Ball et al, Proc Nat Acad Sci USA 2014
DevelopingHumanConnectomeProject
Frontal connections Parietal connections
F = frontal H = hippocampus I = insula LP = lateral parietalM = medial frontal P = Parietal/precuneus S = striatum T = thalamus
The Rich Club in normal newborn infantsDevelopingHumanConnectomeProject
DevelopingHumanConnectomeProject
Thalamocortical connections
Develop during preterm periodDevelop during preterm period
DevelopingHumanConnectomeProject
Functional connections of the Thalamus
Min BK Theoretical Biology and Medical Modelling2010 7:10
The Developing Human Connectome
David Edwards DSc, F Med Sci
November 2, 2014 6
DevelopingHumanConnectomeProject
Thalamic activation and consciousness
N. D. Schiff, et alNature 448, 600-603
DevelopingHumanConnectomeProject
Ball et al, Cortex 2013
Preterm
Term
DifferenceTerm-Preterm
Thalamo-cortical connections
DevelopingHumanConnectomeProject
Preterm at term
Term born control
Thalamo-cortical connections
Ball et al, Cortex 2013
DevelopingHumanConnectomeProject
Colour map showing regions where connectivity is reduced in preterm infants
Effect of preterm birth on thalamo-cortical connections
Ball et al, Cortex 2013
Brain regions where reduced connectivity at term is associated with worse cognitive performance at 2 years
Pazderova et al, ISMRM 2013
Prediction of outcome age 2 years by reduced thalamo-cortical connectivity at term
DevelopingHumanConnectomeProjectFunctional Connections:
co-ordinated activation
• Brain structures activate together when engaged in a task
• Functional connections mapped by functional connectivity Magnetic Resonance Imaging (fcMRI)
Adult fcMRI images courtesy of Marcus Raichle (NeuroImage. 2007;37(4):1083-90)
DevelopingHumanConnectomeProject
The Developing Human Connectome
David Edwards DSc, F Med Sci
November 2, 2014 7
DevelopingHumanConnectomeProject
37Fransson al. (2007) Proc. Natl. Acad. Sci. USA 104, 15531-15536
Resting-state networks in a single infant
DevelopingHumanConnectomeProjectGrowth of motor representation
in human brain
• Resting-state fMRI of spontaneous motor system activity from 29 to 44 weeks gestational age. • Displayed on 4D brain atlas
Doria et al, Proc Natl Acad Sci U S A. 2010;107(46):20015-20
DevelopingHumanConnectomeProject
DevelopingHumanConnectomeProjectGrowth of the default mode and motor
networks
DevelopingHumanConnectomeProject
Functional regions in the cortex at term
Toulmin et al, in progress
DevelopingHumanConnectomeProject
DevelopingHumanConnectomeProjectFunctional connections between
thalamus and cortex
DevelopingHumanConnectomeProject
Toulmin et al, in progress
DevelopingHumanConnectomeProject
Min BK Theoretical Biology and Medical Modelling 2010 7:10
The Developing Human Connectome
David Edwards DSc, F Med Sci
November 2, 2014 8
DevelopingHumanConnectomeProject
Intra-cortical connectivity
• Not included in current connectome projects
• Seemingly intractable
• New methods offer an approach
DevelopingHumanConnectomeProject
McKinstry R C et al. Cereb. Cortex 2002;12:1237-1243
© Oxford University Press
Anisotropy fallsas dendritic trees grow
Changes in neural structure are reflected in diffusion MRI.
DevelopingHumanConnectomeProjectFractional Anisotropy in preterm cortex
Ball et al Proc Nat Acad Sci 110(23):9541-6
DevelopingHumanConnectomeProject
Visualisation of dendritic arborisation in human cortex from 28 to 44 weeks post conception by diffusion MRI Ball et al
Proc Nat Acad Sci 110(23):9541-6
DevelopingHumanConnectomeProject
Visualisation of dendritic arborisation in human cortex from 28 to 44 weeks post conception by diffusion MRI
Ball et al Proc Nat Acad Sci 110(23):9541-6
DevelopingHumanConnectomeProject
p<0.00001
Preterm Infants at term compared to term controls
Ball et al Proc Nat Acad Sci 110(23):9541-6
The Developing Human Connectome
David Edwards DSc, F Med Sci
November 2, 2014 9
DevelopingHumanConnectomeProject
Replication
Gestational age (wks) JA Miller et al. Nature 000, 1-8 (2014) doi:10.1038/nature13185
Areal patterning of gene expression in the developing neocortex.
Gene expression density patterning
JA Miller et al. Nature 000, 1-8 (2014) doi:10.1038/nature13185
Genes associated with white matter development
Boardman et al, Pediatrics 2014
Regions of reduced white matter maturity associated with FADS2
Boardman et al, Pediatrics in press
FADS2 expresssion in 21 week human brain(Allen Developing Brain Atlas)
The Developing Human Connectome
David Edwards DSc, F Med Sci
November 2, 2014 10
Maximal FADS2 expression at 21 weeks
Allen Brain Atlas (www.brainspan.org)
DevelopingHumanConnectomeProject
Example: Fetal MR imaging
Motion correction AnalysisRaw
DevelopingHumanConnectomeProject
Recognition and Thanks
• Serena Counsell• Mary Rutherford• Denis Azzopardi• Daniel Rueckert• Jo Hajnal• Giovanni Montana• Donald Tournier• Paul Aljabar• Gareth Ball• Maria Murgusova• Ahmed Serag• Emma Robinson• Tom Arichi• Hilary Toulmin• Michelle Krishnan• Anand Pandit• Marcus Schirmer
• Christian Beckman (Donders)• Marcus Raichle (St Louis)• Zoltan Molnar (Oxford)• Steve Smith (Oxford)• Tim Behrens (Oxford)
DevelopingHumanConnectomeProject
DevelopingHumanConnectomeProjectThe Rich Club in normal newborn
infants
Ball et al, in progress
DevelopingHumanConnectomeProject
The ‘WU-Minn’ HCP Consortium
Data acquisition sites
Washington University in St Louis:Van Essen (PI) et al. (14)
University of Minnesota:Ugurbil (PI) et al. (6)
Subcontracted institutions (data acquisition and analysis strategies)
University of Oxford
University d’Annunzio
Ernst Strungmann Institute
Advanced MRI Techonologies
Indiana University
Warwick University
37 Investigators total
The Developing Human Connectome
David Edwards DSc, F Med Sci
November 2, 2014 11
HCP Goals• The most accurate in-vivo macro-connectomic
data currently achievable.
• New technologies for data acquisition and connectivity analysis
• New strategies for defining functional areas in-vivo
• A cohort of 1200 subjects with functional and structural connectivity data, but also:
• Genotyping, extensive behavioural testing, task-based fMRI
• All data made easily accessible to the community.
• Major information engineering challenge - Petabytes of data!
DevelopingHumanConnectomeProject
McKinstry R C et al. Cereb. Cortex 2002;12:1237-1243
© Oxford University Press
Fractional anisotropy fallsas dendritic trees grow
DevelopingHumanConnectomeProject
Increasing tissue density due to interneuron and synapse formation causes reduced apparent
diffusion coefficient
McKinstry R C et al. Cereb. Cortex 2002;12:1237-1243
© Oxford University Press
Apparent Diffusion Coefficient fallsas tissue becomes more dense
DevelopingHumanConnectomeProjectApparent Diffusion Coefficient in Preterm Infants
Ball et al PNAS 2013
DevelopingHumanConnectomeProjectThe Developing Human
Connectome Project
The first map of growing connectivity:
– over a critical period of development
– in utero and ex utero
– normal and abnormal
Critical neuroscience questions:
– How does connectivity assemble?
– Genetic and environmental influences?
– Can connectivity explain intractable neurodevelopmental disorders?
July 2009: RFA for Human Connectome Project
(NIH Blueprint)
One $30 million, 5-year grant• Characterize connectivity of healthy adult humans
(diseases, disorders await future projects)
• Use diffusion imaging, R-fMRI, T-fMRI, MEG…
• hundreds of individuals
• Make data freely available
• Provide user-friendly informatics platform
The Developing Human Connectome
David Edwards DSc, F Med Sci
November 2, 2014 12
DevelopingHumanConnectomeProject
Individual data: Rich Club features
DevelopingHumanConnectomeProject
David Edwards
Jo Hajnal
Stephen Smith
Daniel Rueckert
DevelopingHumanConnectomeProject
Lichtman group: (Nature 2007 450, 56-62)
Cortex Hippocampus Cerebellum
Cerebral microstructure
DevelopingHumanConnectomeProjectClarity
DevelopingHumanConnectomeProjectClarity: voxel-level histology
Thornton et al, in progress
DevelopingHumanConnectomeProject
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