Prenatal growth in humans and postnatal brain maturation into late adolescence

Abstract

Prenatal life encompasses a critical phase of human brain development, but neurodevelopmental consequences of normative differences in prenatal growth among full-term pregnancies remain largely uncharted. Here, we combine the power of a withinmonozygotic twin study design with longitudinal neuroimaging methods that parse dissociable components of structural brain development between ages 3 and 30 y, to show that subtle variations of the in utero environment, as indexed by mild birth weight (BW) variation within monozygotic pairs, are accompanied by statistically significant (i) differences in postnatal intelligence quotient (IQ) and (ii) alterations of brain anatomy that persist at least into late adolescence. Greater BW within the normal range confers a sustained and generalized increase in brain volume, which in the cortical sheet, is specifically driven by altered surface area rather than cortical thickness. Surface area is maximally sensitive to BW variation within cortical regions implicated in the biology of several mental disorders, the risk for which is modified by normative BW variation. We complement this near-experimental test of prenatal environmental influences on human brain development by replicating anatomical findings in dizygotic twins and unrelated singletons. Thus, using over 1,000 brain scans, across three independent samples, we link subtle differences in prenatal growth, within ranges seen among the majority of human pregnancies, to protracted surface area alterations, that preferentially impact later-maturing associative cortices important for higher cognition. By mapping the sensitivity of postnatal human brain development to prenatal influences, our findings underline the potency of in utero life in shaping postnatal outcomes of neuroscientific and public health importance.P renatal life encompasses a foundational and universally critical phase of human brain development. Consequently, research aimed at understanding how prenatal influences play out in later life cannot only illuminate mechanisms of fundamental importance to basic developmental neuroscience, but may also have public health implications.Exquisite sensitivity of the developing brain to prenatal environmental insults has been well established through experimental animal models (1). In humans, where experimental approaches are not feasible, numerous observational studies have linked frank insults during prenatal life [as indexed by premature delivery (2); abnormally low birth weight for gestational age (3); and maternal exposure to radiation (4) or starvation (5)], to altered postnatal brain development. However, by virtue of their relative rarity, such frank prenatal insults may be less impactful at the population level than more subtle variations of the in utero environment occurring among the uncomplicated pregnancies from which most people are born (6). Evidence that subtle alterations of the prenatal environment may have meaningful consequences for postnatal development in humans can be found in large-scale epidemiolog...

Neurodevelopmental origins of lifespan changes in brain and cognition

“…We targeted early candidate factors that could potentially impact cortical area and general cognitive function, and hypothesized that such influences on brain and cognition in development would have continuous impacts. The targeted factors included pre-and neonatal biomedical health variables (26,27), specifically length of gestation (28), birth weight (26,27), and Apgar score obtained 5 min after birth (a measure of newborn vital signs) (29), as well as socioeconomic variables (30) [i.e., parental education, income, and single parenthood (31)]. An independent sample of twins was used to estimate the heritability of the surface area of the identified cortical regions, and how much of the phenotypic correlations of cortical area and GCA that could be accounted for by genetic factors.…”

Studying neuroanatomy using MRI

“…Here the inside and outside surfaces of the cortex are segmented using deformable models and measures such as cortical thickness and surface area are extracted [12][13][14] . The diverse anatomical metrics that can be extracted from threedimensional models of the cortical surface capture different developmental processes, and show dissociable correlations with demographic 15,16 , genetic 17,18 , environmental 19 , and clinical 20,21 variables -highlighting the value in moving classical volumetric approaches to anatomical analysis. Surface based methods also provide an improved coordinate system for the cerebral cortex, allowing for smoothing of signal on the cortical sheet and surface based alignment to bring individuals into closer correspondence for statistical comparisons 13,22 .…”

“…Box 3: developmental structural neuroimaging Our first major longitudinal insight into the dynamics of in vivo human brain development came from a structural neuroimaging study 157 , which revealed that the maturational trajectory of human gray matter volume follows a curvilinear "inverted-U", rather than showing a linear progression to adult values. Since this seminal study there has been a steep climb in the number of large-scale longitudinal structural neuroimaging datasets 158 and associated research reports detailing the spatiotemporal heterogeneity of neuroanatomical maturation within the brain 16,159 , and charting how the dynamics of structural brain development can vary as a function of genetic 160 , environmental 19 , demographic (e.g. biological sex 159 ), cognitive 161 and clinical 162 factors.…”

Reply to Segal: Are relationships between birth weight and intelligence quotient variation within twin pairs modulated by patterns of handedness discordance?

“…Intrigued by the converse speculation-that HDlh pairings denote disrupted asymmetry determination-we used in vivo structural neuroimaging data to explicitly test whether within-pair discordance for cerebral asymmetry is greater in HDlh than in HDll pairs. In one structural brain MRI scan for each member of the 17 HD MZ pairs in our sample, we derived measures of local surface area (SA) at ∼40,000 points (vertices) in each cerebral hemisphere as previously described (2). We then quantified pair-wise SA asymmetry concordance by correlating intervertex differences in SA asymmetry [(Left − Right)/(Left + Right) × 0.5] within each twin pair.…”

“…We are grateful for Professor Segal's interesting letter (1), prompting us to delve deeper into a question that was nested within, but not directly addressed by our recent article (2): Are relationships between birth weight (BW) and intelligence quotient (IQ) variation within twin pairs modulated by patterns of handedness discordance? In a sample of 67 monozygotic (MZ) twin pairs (of which ∼40% pairs were discordant for handedness), Professor Segal had found that lower IQ most often segregated with lower BW in handedness-discordant twin pairs when the left-handed member had the lower BW (3).…”