Development of the cerebral cortex / David Van Essen

Development of the cerebral cortex / David Van Essen

Human Cortical Development:
Insights from Imaging
David C. Van Essen
Anatomy & Neurobiology Department
Washington University School of Medicine
OHBM Educational Course
“Anatomy”
June 7, 2015
Honolulu, Hawaii
NICHD, NIMH,
NIH Neuroscience Blueprint
Cortical Development – Insights from Imaging
Prenatal cortical development
•  Morphogenesis of the cortical sheet
•  Cortical arealization
•  Cortical convolutions
Postnatal maturation:
•  Regional expansion & differentiation
•  Abnormal maturation in preterm infants
General features of adult cerebral cortex
Macaque
Human
Surface area (per hemisphere)
110 cm2
1,000 cm2
Thickness
1-3 mm
2-4 mm
Convolutions
Stereotyped
Highly variable
# of cortical areas
~130-140?
~150-200?
Size range
~100x
~100x
Inter-areal pathways
~5,000?
>5,000?
Van Essen et al. (2012a)
Van Essen et al. (2012b)
Markov et al. (2012)
Variability and heritability of cortical folding
W, X = twins
Y, Z = twins
These are two pairs of identical twins
Which are the twin pairs?!
•  Some regions are consistently folded (e.g., central sulcus)
•  Other regions are highly variable (e.g., posterior ITS)
•  Folding patterns are heritable, but only modestly so (Van Essen et al., OHBM 2014)
Botteron, Dierker, Todd et al., 2008
Key issues in Cortical Morphogenesis
•  Why is the cortex a sheet, with variable thickness?
•  What determines cortical surface area?
•  Why and how does the cortex fold?
•  Why is human cortical folding so variable?
•  How does the cortex become parcellated?
•  How are specific connections established?
Morphogenesis is driven by:
•  Cell proliferation, migration, differentiation
•  Physical forces: tension & pressure (D’Arcy Thompson, 1917)
Why is the cortex a sheet, whereas nuclei are blobs ?
•  Observation: Neuronal processes generate mechanical tension [1]
•  Hypothesis: radial anisotropies (dendrites, axons, glia) lead to sheets
Isotropic cellular architecture leads to blob-like nuclei [2]
[1] Bray (1984); Dennerll et al., (1988)
[2] Van Essen (Nature, 1997)
Cortical areal differentiation I.
Early stages in mouse:
•  A protomap in cortical progenitors (VZ) (O’Leary et al., Neuron, 2007)
•  Gradients of morphogens in cortical plate and ventricular zone
(TGF8, Emx2, Nr2f1, Pax6, Eomes, TBR1…)
Human
Mouse
Cortical areal differentiation I.
Early stages in mouse:
•  A protomap in cortical progenitors (VZ) (O’Leary et al., Neuron, 2007)
•  Gradients of morphogens in cortical plate and ventricular zone
(TGF8, Emx2, Nr2f1, Pax6, Eomes, TBR1…)
•  Many similarities between human and mouse (Miller et al., Nature, 2014)
Human
Mouse
Brainspan project:
Human 15 week, 21 week - near
peak of cortical neurogenesis
•  Broad fronto-temporal gradients
•  No sharp boundaries or ‘areaspecific patches’
Cortical areal differentiation II.
How does this….
lead to this?!!
Later stages: differentiation of the full areal mosaic
•  Additional morphogens and gradients??
•  Area-specific markers?? (mystery molecules - micro-RNA’s?)
•  Activity dependence??
Emergence of new areas in humans?
•  Areal duplication and divergence? (e.g., Grove et al. 2012)
How is specificity of long-distance connections established?
Human cortical folding mainly in third trimester
Hill et al. (J. Neuroscience, 2010)
Overlaps with formation of connections
Coogan & Van Essen (1996)
What causes convolutions?
Lunate
sulcus
•  Earliest V1-V2 connections ~E108
(Coogan & Van Essen, 1996)
•  Folding brings V1 and V2 retinotopic maps
closer together, roughly in register
•  How - by tension along axons??!!
Tension-based cortical folding:
•  Strongly interconnected regions win (gyrus in between)
•  Weakly interconnected regions lose (sulcus in between)
•  Variable folding may reflect variabililty in areal sizes and/or connectivity
Van Essen (Nature, 1997)
Alternative mechanisms proposed (cf. Welker, 1990)
Richman, 1975
Buckling (differential laminar growth)
(Richman, 1975; Toro & Burnod, 2005;
Ronan et al., Cerebral Cortex, 2013)
Constraints imposed by skull
(LeGros Clark, 1945; but see Barron, 1950)
Differential proliferation in SVZ
(Kriegstein et al., 2006; Reillo et al., 2011)
Toro & Burnod, 2005
Differential proliferation in Outer SubVentricular Zone
Mouse
Ferret
•  Thick OSVZ in gyrencephalic species
•  Intermediate Radial Glial (IRG) cells
produce neurons + glia
Reillo et al. (Cerebral Cortex, 2011)
More IRG cells, thicker OSVZ below gyri
Plausibility of cortical folding mechanisms
Differential proliferation:
•  Plausible for primary folds (before proliferation ceases)
•  Implausible for tertiary (irregular) human folds
Tension-based folding:
•  Neurites generate tension (Bray, 1984; Dennerll et al.,1988; but see Xu et al, 2010)
•  Broad explanatory power (sheets and folds)
•  Wiring length minimization comes for free!
Multiple mechanisms? (as often in biology)
Cortical Development – Insights from Imaging
Prenatal cortical development
•  Morphogenesis of the cortical sheet
•  Cortical arealization
•  Cortical convolutions
Postnatal maturation:
•  Regional expansion & differentiation
•  Abnormal maturation in preterm infants
MR contrast changes during early development
T2w
Gestational
weeks
Serag et al. (Neuroimage, 2012)
Leroy et al. (PLoS, 2011)
•  Prenatal & early postnatal: low tissue contrast, nonuniform
•  White matter myelination: mainly postnatal
•  Regional differences in myelination onset
Postnatal cortical expansion: adults vs healthy term infants
Hill et al. (J. Neurosci, 2010)
Hemispheric asymmetries evident at birth
Postnatal cortical expansion: large regional differences
Adult/neonatal surface area ratio
3-fold overall
postnatal
expansion
High-expansion:
frontal, parietal, lateral temporal
Low-expansion:
occipital, medial temporal, parietal
Hill et al. (PNAS, 2010)
Postnatal differences are
discernible in individuals
Postnatal cortical expansion occurs mainly in the first 2 years
Li et al. (Cerebral Cortex, 2012)
Hill et al. (PNAS, 2010)
Adult vs neonate
•  Similarities exceed differences
•  Differences might be methodological or neurobiological
Postnatal dendritic arbor maturation
Human prefrontal cortex
Layer 3C
Petanjek et al.
(Cerebral Cortex, 2008)
Layer 5
•  Dendritic arbors expand in early postnatal development
•  Major regional differences, pruning in some regions (Elston et al., 2009)
Myelin maps in cerebral cortex
Sensory-motor
strip
T1-weighted
Divide and conquer:
T2-weighted
image
T1w/T2w ratio
brighter
darker
Auditory
MT+
darker
brighter
Myelin content
Low
Glasser & Van Essen (2011); Van Essen & Glasser (2013)
High
Early myelination:
Heavy adult myelination
Many features correlate with postnatal expansion pattern
Myelin map
Postnatal
Human/Macaque
Cortical
thickness
Regions of high postnatal expansion:
•  expanded recently in human evolution
•  tend to have:
! 
! 
! 
! 
! 
lighter myelination
delayed myelination
thicker cortex
larger, late-developing dendritic arbors
lower neuronal density
Onset of
myelination
Abnormal cortical maturation in premature infants
Immature folding in some
term-equivalent infants
Selective vulnerability of lateral
temporal cortex?
Cortical morphometry in very preterm (VPT) children
studied at age 7 years (Zhang et al., 2015)
•  Cortical surface area: 9% smaller in VPT vs TC
•  Shallower Superior Temporal Sulcus in VPT
•  Regional differences in relative surface area
• 
• 
VPT reduced in parietal operculum
VPT expanded, more convoluted in cingulate cortex
Anatomy of Cortical Development & Maturation
•  Rapid prenatal development (3rd trimester)
•  Postnatal maturation over many years
•  Regional sensitivity to perturbation and injury
•  Insights into individual variability, role of experience
•  Brain connectivity and function during development:
•  Human Connectome Project (HCP,
• 
• 
• 
http://www.humanconnectome.org)
Major advances in data acquisition and analysis
A baseline for studies of development, aging, and disease
Lifespan pilot project (children, older adults)
•  Three NIH Lifespan RFAs: Baby; Development; Aging
•  Developing Human Connectome Project (dHCP)
Prenatal brain development (D. Edwards et al., Kings/Imperial/Oxford)
http://www.developingconnectome.org
ACKNOWLEDGMENTS
Donna Dierker
Matt Glasser
John Harwell
Erin Reid
Terrie Inder
Jeff Neil
Jim Alexopoulos
Jason Hill
Erin Engelhardt
Yuning Zhang
Washington University
University of Minnesota
Oxford University
Kamil Ugurbil (co-PI); 101 HCP consortium members
HCP funding from the NIH Blueprint!
Saint Louis University
University d’Annunzio
Indiana University
Warwick University
Ernst Strungmann Institute
Radboud University
Duke University