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Original Investigation |

Structural Growth Trajectories and Rates of Change in the First 3 Months of Infant Brain Development ONLINE FIRST

Dominic Holland, PhD1,2; Linda Chang, MD3; Thomas M. Ernst, PhD3; Megan Curran2; Steven D. Buchthal, PhD3; Daniel Alicata, MD3; Jon Skranes, MD3,4; Heather Johansen3; Antonette Hernandez3; Robyn Yamakawa3; Joshua M. Kuperman, PhD2,5; Anders M. Dale, PhD1,2,5
[+] Author Affiliations
1Department of Neurosciences, University of California, San Diego, La Jolla
2Multimodal Imaging Laboratory, University of California, San Diego, La Jolla
3Department of Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu
4Department of Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology, Trondheim, Norway
5Department of Radiology, University of California, San Diego, La Jolla
JAMA Neurol. Published online August 11, 2014. doi:10.1001/jamaneurol.2014.1638
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Importance  The very early postnatal period witnesses extraordinary rates of growth, but structural brain development in this period has largely not been explored longitudinally. Such assessment may be key in detecting and treating the earliest signs of neurodevelopmental disorders.

Objective  To assess structural growth trajectories and rates of change in the whole brain and regions of interest in infants during the first 3 months after birth.

Design, Setting, and Participants  Serial structural T1-weighted and/or T2-weighted magnetic resonance images were obtained for 211 time points from 87 healthy term-born or term-equivalent preterm-born infants, aged 2 to 90 days, between October 5, 2007, and June 12, 2013.

Main Outcomes and Measures  We segmented whole-brain and multiple subcortical regions of interest using a novel application of Bayesian-based methods. We modeled growth and rate of growth trajectories nonparametrically and assessed left-right asymmetries and sexual dimorphisms.

Results  Whole-brain volume at birth was approximately one-third of healthy elderly brain volume, and did not differ significantly between male and female infants (347 388 mm3 and 335 509 mm3, respectively, P = .12). The growth rate was approximately 1%/d, slowing to 0.4%/d by the end of the first 3 months, when the brain reached just more than half of elderly adult brain volume. Overall growth in the first 90 days was 64%. There was a significant age-by-sex effect leading to widening separation in brain sizes with age between male and female infants (with male infants growing faster than females by 200.4 mm3/d, SE = 67.2, P = .003). Longer gestation was associated with larger brain size (2215 mm3/d, SE = 284, P = 4×10−13). The expected brain size of an infant born one week earlier than average was 5% smaller than average; at 90 days it will not have caught up, being 2% smaller than average. The cerebellum grew at the highest rate, more than doubling in 90 days, and the hippocampus grew at the slowest rate, increasing by 47% in 90 days. There was left-right asymmetry in multiple regions of interest, particularly the lateral ventricles where the left was larger than the right by 462 mm3 on average (approximately 5% of lateral ventricular volume at 2 months). We calculated volume-by-age percentile plots for assessing individual development.

Conclusions and Relevance  Normative trajectories for early postnatal brain structural development can be determined from magnetic resonance imaging and could be used to improve the detection of deviant maturational patterns indicative of neurodevelopmental disorders.

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Figure 1.
Infant Atlas and Automatically Segmented Magnetic Resonance Images

A, Cross-sections through T1 (upper) and T2 (lower) atlas images. B, Examples of automatic segmentation. Upper row: 5-day-old male neonate (brain volume, 3.1 × 105 mm3; 30% of elderly adult brain volume); lower row, 117-day-old male infant with a brain more than twice as large (brain volume, 6.6 × 105 mm3; 65% of adult brain volume). Color key: yellow, hippocampus; pink, putamen; light blue, caudate; medium blue, pallidum; light green, thalamus; purple, ventricles; dark green, cerebellum; gray, brain stem; brown, rest of whole-brain parenchyma.

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Figure 2.
Whole-Brain Growth Trajectories, Daily Growth Rates, and Volume-for-Age Percentile Plots

A, Spaghetti plot showing whole-brain volume for 39 male and 48 female infants (94 and 117 time points, respectively) during the first 3 months of postnatal life, along with generalized additive mixed model (GAMM) fits to the data (dark lines, from the Equation), and 95% CIs (shaded regions); see also eFigure 2 in the Supplement. B, Daily growth rate for the whole brain during the first 3 months of postnatal life (for male and female infants combined). The dashed line is the gradient of a GAMM fit for whole-brain volume trajectory; the solid line is a GAMM fit to centered linear estimates of the growth rates (between each subject’s neighboring data points) from the longitudinal data only. Whole-brain volume-by age percentile plots for boys (C) and girls (D) (see also eFigure 3B and 3D in the Supplement); these plots can be used when controlling for an infant’s head circumference and gestational age at birth.

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