the developing human connectome - vermont oxford network · 2014-10-27 · the developing human...

The Developing Human Connectome

David Edwards DSc, F Med Sci

November 2, 2014 1

DevelopingHumanConnectomeProject

David Edwards

Jo Hajnal

Stephen Smith

Daniel Rueckert


I have no disclosures to make


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


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Behrens & Glasser (unpublished)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



Structural connections: the wiring diagram of the brain

• White matter tracts carry information

• Visualised in live humans using diffusion Magnetic Resonance Imaging (dMRI)


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



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




White matter tracts in a newborn infant



4-Dimensional brain atlas

Kulisova-Murgusova et al.Neuroimage 2011 54(4):2750-63

Serag et al Neuroimage2012 59(3):2255-65



November 2, 2014 3


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


DevelopingHumanConnectomeProjectStructural connections:

preliminary data

• Coarse connectome

– Environmental influences

• Voxel level

– Rich club organisation

– Thalamocortical Connectivity

• Intra-cortical connectivity


DevelopingHumanConnectomeProjectInitial sparse, coarse, consensus

connectome for infants born preterm

Pandit et al, Cerebral Cortex 2013



Rich club organization.

Collin G et al. Cereb. Cortex 2013;cercor.bht064

© The Author 2013. Published by Oxford University Press.



DevelopingHumanConnectomeProjectEffect of growth and preterm birth on

connectivity





November 2, 2014 4


Connections growing most strongly


DevelopingHumanConnectomeProjectEffect of growth and preterm birth on

connectivity



Node size

smaller cortical nodes



500 randomly distributed regions of ~equal size (250 per hemisphere)

Repartition And Repeat

Tractography

Iterated random samplingDevelopingHumanConnectomeProject


Group data: Rich Club features

Rich Club Coefficient

Normalised Rich Club Coefficient


Rich Club:40 weeks gestation


Ball et al, Proc Nat Acad Sci USA 2014



November 2, 2014 5


Rich Club 30 weeks gestation





Changes 30 to 40 weeks



Euclidian lengths of connections



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


Thalamocortical connections

Develop during preterm periodDevelop during preterm period


Functional connections of the Thalamus

Min BK Theoretical Biology and Medical Modelling2010 7:10



November 2, 2014 6


Thalamic activation and consciousness

N. D. Schiff, et alNature 448, 600-603


Ball et al, Cortex 2013

Preterm

Term

DifferenceTerm-Preterm

Thalamo-cortical connections


Preterm at term

Term born control

Thalamo-cortical connections



Colour map showing regions where connectivity is reduced in preterm infants

Effect of preterm birth on thalamo-cortical connections


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)




November 2, 2014 7


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


DevelopingHumanConnectomeProjectGrowth of the default mode and motor

networks


Functional regions in the cortex at term

Toulmin et al, in progress


DevelopingHumanConnectomeProjectFunctional connections between

thalamus and cortex


Toulmin et al, in progress


Min BK Theoretical Biology and Medical Modelling 2010 7:10



November 2, 2014 8


Intra-cortical connectivity

• Not included in current connectome projects

• Seemingly intractable

• New methods offer an approach


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


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


Visualisation of dendritic arborisation in human cortex from 28 to 44 weeks post conception by diffusion MRI



p<0.00001

Preterm Infants at term compared to term controls




November 2, 2014 9


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)



November 2, 2014 10

Maximal FADS2 expression at 21 weeks

Allen Brain Atlas (www.brainspan.org)


Example: Fetal MR imaging

Motion correction AnalysisRaw


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)


DevelopingHumanConnectomeProjectThe Rich Club in normal newborn

infants

Ball et al, in progress


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



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!




Fractional anisotropy fallsas dendritic trees grow


Increasing tissue density due to interneuron and synapse formation causes reduced apparent

diffusion coefficient



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



November 2, 2014 12


Individual data: Rich Club features


David Edwards

Jo Hajnal

Stephen Smith

Daniel Rueckert


Lichtman group: (Nature 2007 450, 56-62)

Cortex Hippocampus Cerebellum

Cerebral microstructure

DevelopingHumanConnectomeProjectClarity

DevelopingHumanConnectomeProjectClarity: voxel-level histology

Thornton et al, in progress


the developing human connectome - vermont oxford network · 2014-10-27 · the developing human...

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