Abnormal Cortical Development after Premature Birth Shown by Altered Allometric Scaling of Brain Growth

BACKGROUND: We postulated that during ontogenesis cortical surface area and cerebral volume are related by a scaling law whose exponent gives a quantitative measure of cortical development. We used this approach to investigate the hypothesis that premature termination of the intrauterine environment by preterm birth reduces cortical development in a dose-dependent manner, providing a neural substrate for functional impairment. METHODS AND FINDINGS: We analyzed 274 magnetic resonance images that recorded brain growth from 23 to 48 wk of gestation in 113 extremely preterm infants born at 22 to 29 wk of gestation, 63 of whom underwent neurodevelopmental assessment at a median age of 2 y. Cortical surface area was related to cerebral volume by a scaling law with an exponent of 1.29 (95% confidence interval, 1.25–1.33), which was proportional to later neurodevelopmental impairment. Increasing prematurity and male gender were associated with a lower scaling exponent (p < 0.0001) independent of intrauterine or postnatal somatic growth. CONCLUSIONS: Human brain growth obeys an allometric scaling relation that is disrupted by preterm birth in a dose-dependent, sexually dimorphic fashion that directly parallels the incidence of neurodevelopmental impairments in preterm infants. This result focuses attention on brain growth and cortical development during the weeks following preterm delivery as a neural substrate for neurodevelopmental impairment after premature delivery

Effect of Increasing Prematurity on Brain Growth and Neurodevelopmental Function

<div><p>(A) Scaling exponent <i>α</i> determined for each birth week cohort (mean and 95% confidence intervals for the mean), showing decreased values at earlier gestations, giving an intuitive univariate visualization of the generalized least-squares random effects modelling.</p> <p>(B) Neurodevelopmental outcome for infants born in these weeks, showing both the DQ for each individual assessment (hollow circles) and the mean value for each birth week (horizontal bar) with regression line and 95% confidence limits for the population. It can be seen to increase with gestational age at birth (<i>p <</i> 0.05). The single filled circle denotes the infant presented in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0030265#pmed-0030265-g002" target="_blank">Figure 2</a>.</p></div

Annotated MR Image Showing Definition of Cortical Boundary

<p>Annotated MR Image Showing Definition of Cortical Boundary</p

Cerebral Volume and Surface Area Growth in Preterm Infants

<div><p>(A) Values for cerebral volume and cortical surface area for 113 infants imaged serially between 23 and 48 wk gestation (274 scans) displayed on log-log coordinates and related to gestational age at scan, showing linear relationships for both variables.</p> <p>(B) Scaling of cortical surface area relative to cerebral volume shown as a scatter plot in log-log coordinates of the cortical surface area <i>s</i> against cerebral volume <i>v</i> determined from each of these 274 scans. The linear relationship apparent for volumes greater than about 45 cm³ indicates a power law scaling of the form <i>s</i> = <i>kv^α</i>, where <i>α</i> is the scaling exponent and <i>k</i> is a constant. For a three-dimensional object that maintains its shape with changing size, the exponent <i>α</i> would take the value 2/3 (since area scales as length squared and volume as length cubed). For the data in this plot, in contrast, a good fit (for <i>v</i> > 45 cm³) is obtained with <i>α</i> = 1.29 (95% confidence interval 1.25–1.33).</p></div

Serial MR Imaging of Brain Growth in a Normal Female Preterm Infant

<p>When this infant was born at 25 weeks gestational age she weighed 710 g. The images show slices through the brain at the mid-ventricular level and at the level of the centrum semiovale from six of the eight MR images obtained between 26 and 39 wk gestational age; images obtained at 30 and 38 weeks are omitted for graphical clarity. Measured values for cerebral volume (triangles) and cortical surface area (circles) are related to relevant image pairs by straight lines. The insert displays a scatter plot in log-log coordinates of cortical surface area and cerebral volume (diamonds), showing a linear relationship that indicates power law scaling of cortical surface area relative to cerebral volume in this individual.</p

Cortical Surface Area and Cerebral Volume of Preterm Infants

<p>A total of 113 preterm infants, born between 23 and 30 weeks gestation, were measured for cortical surface area and cerebral volume over the period from birth to 48 weeks gestational age.</p