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Structural brain imaging is a window on postnatal brain development in children
Terry Jernigan
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What We Thought We Knew About Brain Structure
• Neuronal populations and their connections (the basic architecture of the brain) are established during the prenatal period.
• Soon after birth oligodendrocytes proliferate, differentiate, and wrap the connecting axons with insulating, fatty, sheaths of myelin.
• This more or less completes the development of the hardware, and little additional growth of the brain occurs after age 5 or 6.
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“Brain structure is adult at approximately age 5.”
Structural MRI of young child from NIH Brain Development Study
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Brain Morphometry
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Predictions Based on Conventional Views of Brain
Morphology
• Adult brain structure in school-aged children.
• Stable brain morphological characteristics across childhood, adolescence, and adult years.
• Atrophy of some brain structures in old age.
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Age-Related Alterations ofNormalized Cerebral Gray Matter Volume
.4
.45
.5
.55
.6
.65
.7
.75
.8
0 20 40 60 80 100
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Mapping of Cortical Thinning with Longitudinal MRI Data
Gogtay et al., PNAS, 2004
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Longitudinal Mapping of Cortical Thickness and Brain Growth in Normal Children
(Sowell et al.,J. Neurosci., 2004)
Widespread cortical thinning, and focal areas of cortical thickening observed longitudinally in children over 2 years, from 7 to 9.
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Age-Associated Alterations in Volumes of Subcortical Structures
-2
-1
0
1
2
3
Thalamus
0 10 20 30 40 50 60 70 80 90 100
Age
-2
-1
0
1
2
3
N. Accumbens
0 10 20 30 40 50 60 70 80 90 100
Age
Thalamus
N.Accumbens
Hippocampus
-3
-2
-1
0
1
2
Hippocampus
0 10 20 30 40 50 60 70 80 90 100
Age
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Why don’t young brains appear atrophied?
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White Matter Growth Associated with Post-natal Proliferation of Oligodendrocytes and Myelin
Deposition
-3
-2
-1
0
1
2
Cerebral WM
0 10 20 30 40 50 60 70 80 90 100
Age
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Post-Natal Myelination is Well Visualized on MRI :
Myelinating Fiber Tracts from 3 to 12 Months
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Summary• During the first 2-3 decades of life, age-related tissue
alterations, presumably related to brain maturation, can be observed with morphometry.
• Though the first evidence came in the form of apparent changes in the morphology of gray matter structures, it was suspected that much of the change was directly, or indirectly, related to continuing myelination and fiber tract development.
• However, until recently, further investigation of fiber tract
maturation was limited by the lack of sensitivity to white matter structure with existing MR methods.
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Diffusion imaging provides new information about brain
connectivity
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Diffusion Tensor Imaging
• Measures diffusion (motion) of protons in water molecules.
• Magnitude and direction of proton motion within a voxel can be described by a “tensor”.
• Proton diffusion in “free” water (or cerebrospinal fluid) is isotropic, and also tends to be relatively isotropic in gray matter.
• The linear structure of fiber tracts hinders proton diffusion and produces anisotropy.
BA
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Diffusion Tensor Imaging
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Hypothetical Explanation of Changes on Diffusion Imaging During Brain
Development
• During development, increasing myelination and axon calibre,
• result in less extracellular free water,
• which results in lower diffusivity
• and increased fractional anisotropy (FA) in brain fiber tracts.
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Neural Architectural Variability
• Examined closely, the brain exhibits a complex pattern of age-associated tissue alterations well into adulthood.
• There is substantial variability among individuals at all ages.
• The questions:– What is the source of this variability?
• Genetically-mediated difference in patterning of brain (cortical arealization, strength of connectivity, etc)?
• Genetically-mediated status of maturation?• Experience-related neuroplastic effects (short term, long term)?• Interactions between experience and phase of maturation?
– Is this variability functionally meaningful?
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Variability in neural architecture is related to behavioral phenotypic differences,
especially (but not exclusively) in children.
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Microstructural Correlates of Infant FunctionalDevelopment: Example of the Visual Pathways
(Dubois et al., J. Neurosci, 2008)
Latency of the P1 component of the Visual Evoked Potential correlated with FA in the optic radiations, independent of chronological age, in 5 - 17 week old infants.
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R2 = 0.406
0.25
0.5
70 100 1300.25
0.5
70 100 130
0.25
0.5
70 100 130
y = 0.0026x + 0.1966R2 = 0.4199
0.25
0.5
70 100 130
Standardized Word ID
Standardized Digit Recall
“Double Dissociation” in Correlation Patterns
Niogi, S. & McCandliss, B.D.(2006) Neuropsychologia
Left SCR
Bilateral ACR
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Study of Behavioral Individual Differences in Danish Children
• 95 school children, 7-13 years old• sMRI, DTI, cognitive testing• Inhibitory function measured with
CANTAB Stop Signal Task (SSRT)• Spatial working memory measured
with CANTAB self-ordered search task
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Stop Signal Task
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FA in Right IFG and Right pre-SMA Both Contribute to Prediction of Inhibitory Function in Children
(Madsen SK, Baare WFC, Hansen MV, Skimminge A, Ejersbo LR, Ramsøy TZ, Gerlach C, Åkeson P, Paulson OB, Jernigan TL ., 2009)
• Individual differences in children’s inhibitory function is related to FA differences within the neural circuit previously implicated in SST performance.
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Spatial Working Memory Task
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Spatial Working Memory Performance Related to FA in Superior Longitudinal Fasciculus
(Vestergaard M, Madsen KS, Baare WFC, Skimminge A, Ejersbo LR, Ramsøy TZ, Gerlach C, Åkeson P, Paulson OB, Jernigan TL. .,
Under Review)
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Brain microstructural correlates of visuospatial choice reaction time in children
KS Madsen, WFC Baaré, A Skimminge, M Vestergaard, HR Siebner
and TL Jernigan
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Behavioral Variability is Related to Neural Variability(particularly in brain connections)
• Performance on cognitive tasks across multiple domains correlates with fiber tract structural characteristics.
• The associations remain after controlling for age and global parameters.
• It appears that profiles of behavioral attributes are reflected in profiles across brain fiber pathways.
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How do we interpret these associations between the neural and the behavioral differences?
• In children, could they arise because of differences (among children of similar age) in the pace of biological development of the brain?
• To what extent do they reflect functional effects of genetically-mediated differences in neural connectivity – or in the pace of development of these neural connections?
• To what extent are they driven by neuroplastic effects of experience, practice, training, and other factors that affect neural activity within brain systems?
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Are the associations related to activity-dependent neuroplastic
changes in the tissue?
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Learning to Juggle Produces Transient Change in Cortical and Tract Morphology(Draganski et al., Nature, 2004; Scholz et al.,
2009)
• Normal volunteers with no juggling skills were scanned at baseline.• Subjects were taught a simple juggling task to criterion and re-
scanned.• After 3 months (Draganski et al.) or 4 week (Scholz et al.) without
practice, jugglers were scanned a third time.• Focal increases in gray matter were observed in middle temporal and
left intraparietal sulcus areas, FA was increased in underlying white matter, and these were apparently diminished after 3 months.
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Altering Cortical Connectivity: Remediation-Induced Changes
in the White Matter of Poor ReadersTimothy A. Keller and Marcel Adam Just, Neuron, 2009
A: Areas where FA increased in poor readers after remediation.
B: Areas where FA differed between good and poor readers at baseline
• 8-10 year old children show apparent intervention-linked alterations of FA in fiber tracts.
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Genes Exert Strong Effects on Brain Morphology
• Twin studies have revealed high heritability of brain morphology.
• We recently reported that 2 attributes of the neural architecture, cortical surface area and cortical thickness are both highly heritable, but exhibit no genetic association.
• Genetic effects on developmental trajectories have not yet been examined.
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VETSA Study of TwinsRimol et al. 2010
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Pattern of Cortical Arealization Associated with Common Genetic Variation (in males)
MECP2 SNP rs2239464(Joyner et al.,PNAS, 2009)
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Heritability of Fiber Tract Structure (Chiang et al., 2009)
• FA in brain fiber tracts exhibits heritability – i.e., it is more similar between identical (monozygotic) twins than between fraternal (dizygotic) twins.
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Conclusions• There is evidence that biological
development of brain tissues continues throughout childhood and adolescence.
• The biological changes can be linked to individual differences in behavior in developing children.
• There is much left to learn about the meaning of these associations – i.e., about how genetic variation, experience, and other environmental factors interact to influence the developing mental characteristics (and individuality) of a child.
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