Automatic segmentation of the hippocampus for preterm neonates from early-in-life to term-equivalent age

Abstract

Introduction: The hippocampus, a medial temporal lobe structure central to learning and memory, is particularly vulnerable in preterm-born neonates. To date, segmentation of the hippocampus for preterm-born neonates has not yet been performed early-in-life (shortly after birth when clinically stable). The present study focuses on the development and validation of an automatic segmentation protocol that is based on the MAGeT-Brain (Multiple Automatically Generated Templates) algorithm to delineate the hippocampi of preterm neonates on their brain MRIs acquired at not only term-equivalent age but also early-in-life.

Methods: First, we present a three-step manual segmentation protocol to delineate the hippocampus for preterm neonates and apply this protocol on 22 early-in-life and 22 term images. These manual segmentations are considered the gold standard in assessing the automatic segmentations. MAGeT-Brain, automatic hippocampal segmentation pipeline, requires only a small number of input atlases and reduces the registration and resampling errors by employing an intermediate template library. We assess the segmentation accuracy of MAGeT-Brain in three validation studies, evaluate the hippocampal growth from early-in-life to term-equivalent age, and study the effect of preterm birth on the hippocampal volume. The first experiment thoroughly validates MAGeT-Brain segmentation in three sets of 10-fold Monte Carlo cross-validation (MCCV) analyses with 187 different groups of input atlases and templates. The second experiment segments the neonatal hippocampi on 168 early-in-life and 154 term images and evaluates the hippocampal growth rate of 125 infants from early-in-life to term-equivalent age. The third experiment analyzes the effect of gestational age (GA) at birth on the average hippocampal volume at early-in-life and term-equivalent age using linear regression.

Results: The final segmentations demonstrate that MAGeT-Brain consistently provides accurate segmentations in comparison to manually derived gold standards (mean Dice's Kappa > 0.79 and Euclidean distance <1.3 mm between centroids). Using this method, we demonstrate that the average volume of the hippocampus is significantly different (p < 0.0001) in early-in-life (621.8 mm(3)) and term-equivalent age (958.8 mm(3)). Using these differences, we generalize the hippocampal growth rate to 38.3 ± 11.7 mm(3)/week and 40.5 ± 12.9 mm(3)/week for the left and right hippocampi respectively. Not surprisingly, younger gestational age at birth is associated with smaller volumes of the hippocampi (p = 0.001).

Conclusions: MAGeT-Brain is capable of segmenting hippocampi accurately in preterm neonates, even at early-in-life. Hippocampal asymmetry with a larger right side is demonstrated on early-in-life images, suggesting that this phenomenon has its onset in the 3rd trimester of gestation. Hippocampal volume assessed at the time of early-in-life and term-equivalent age is linearly associated with GA at birth, whereby smaller volumes are associated with earlier birth.

Keywords: Early-in-life; Hippocampus; MAGeT-Brain; MRI; Preterm neonates; Segmentation.

Fig. 1

Axial images from T1-weighted MR of the same preterm-born child at different ages demonstrating rapid brain growth and maturation which occurred from 29 weeks GA to 2 years of age. a. 29 weeks gestational age (GA); b. 40 weeks GA; c. 2 years. The white and gray matter contrast on images acquired at 29 and 40 weeks of GA is the inverse of that on the 2 year image.

Fig. 2

3-Step manual segmentation protocol. The estimation of the hippocampal boundaries was initially performed using the coronal view and then refined using the sagittal view. 3D surface model of the segmented hippocampus was constructed for the final inspection of segmentation.

Fig. 3

Representative segmentations of the hippocampus for each coronal slice of an example subject. i. The lateral border defined by the inferior horn of the lateral ventricle; ii. the lateral ventricle and iii. the location where the subiculum of the hippocampus meets the ambient cistern defines the medial border.

Fig. 4

Mean Dice's Kappa between the gold standard manual segmentations and MAGeT-Brain hippocampal segmentations with 187 different parameter settings (5–15 atlases and 5–21 templates) over 10 folds for 22 early-in-life images (top), 22 term images (middle), and 42 mixed images (bottom). Error bars indicate standard error.

Fig. 5

Mean Euclidean distance between centroids of manually segmented hippocampi and those of MAGeT-Brain segmentations with 187 parameter settings over 10 folds for 22 early-in-life images (top), 22 term images (middle), and 42 mixed images (bottom). Error bars indicate standard error.

Fig. 6

Bland–Altman plots of MAGeT-Brain vs. manually segmented hippocampal volumes for 22 early-in-life images (top), 22 term images (middle), and 42 mixed images (bottom). The overall mean difference in volume and limits of agreement (±1.96SD) are shown by dashed horizontal lines. Linear fit lines are shown for each group.

Fig. 7

Bland–Altman plots of the centroid location of MAGeT-Brain vs. manually segmented hippocampi (left & right, x, y, z) in the early-in-life (20 images), term (20 images), and mixed (38 images) groups. The overall mean difference in each coordinate direction and limits of agreement (±1.96SD) are shown by dashed horizontal lines. Linear fit lines are shown for each group.

Fig. 8

Comparison of manual hippocampal segmentations with MAGeT-Brain-based hippocampal segmentations on the 22 early-in-life images of very preterm-born infants. Red: hippocampal regions segmented either manually or by MAGeT-Brain; green: the common regions of manual and MAGeT-Brain segmentations. Magenta arrows point to areas over-estimated by MAGeT-Brain; blue arrows point to areas under-estimated by MAGeT-Brain. Kappa values are at bottom right corners.

Fig. 9

Comparison of manual hippocampal segmentations with MAGeT-Brain-based hippocampal segmentations on the 22 term images of very preterm-born infants (sagittal view). Red: hippocampal regions segmented either manually or by MAGeT-Brain; green: the common regions of manual and MAGeT-Brain segmentations. Magenta arrows point to areas over-estimated by MAGeT-Brain; blue arrows point to areas under-estimated by MAGeT-Brain. Kappa values are at bottom right corners.

Fig. 10

Impact of premature birth on hippocampal volume assessed within the first weeks of life and at term-equivalent age in very preterm born neonates. Data represent the average left and right hippocampal volumes (mm³) acquired at early-in-life and those at term-equivalent age for each neonate. Smaller hippocampal volume is associated with an earlier GA at birth (T = 17.9, p < 0.0001, adjusting for days of life [DOL] at MRI).