Impaired hippocampal development and outcomes in very preterm infants with perinatal brain injury

Abstract

Preterm infants are at high risk for brain injury during the perinatal period. Intraventricular hemorrhage and periventricular leukomalacia, the two most common patterns of brain injury in prematurely-born children, are associated with poor neurodevelopmental outcomes. The hippocampus is known to be critical for learning and memory; however, it remains unknown how these forms of brain injury affect hippocampal growth and how the resulting alterations in hippocampal development relate to childhood outcomes. To investigate these relationships, hippocampal segmentations were performed on term equivalent MRI scans from 55 full-term infants, 85 very preterm infants (born ≤32 weeks gestation) with no to mild brain injury and 73 very preterm infants with brain injury (e.g., grade III/IV intraventricular hemorrhage, post-hemorrhagic hydrocephalus, cystic periventricular leukomalacia). Infants then underwent standardized neurodevelopmental testing using the Bayley Scales of Infant and Toddler Development, 3rd edition at age 2 years, corrected for prematurity. To delineate the effects of brain injury on early hippocampal development, hippocampal volumes were compared across groups and associations between neonatal volumes and neurodevelopmental outcomes at age 2 years were explored. Very preterm infants with brain injury had smaller hippocampal volumes at term equivalent age compared to term and very preterm infants with no to mild injury, with the smallest hippocampi among those with grade III/IV intraventricular hemorrhage and post-hemorrhagic hydrocephalus. Further, larger ventricle size was associated with smaller hippocampal size. Smaller hippocampal volumes were related to worse motor performance at age 2 years across all groups. In addition, smaller hippocampal volumes in infants with brain injury were correlated with impaired cognitive scores at age 2 years, a relationship specific to this group. Consistent with our preclinical findings, these findings demonstrate that perinatal brain injury is associated with hippocampal size in preterm infants, with smaller volumes related to domain-specific neurodevelopmental impairments in this high-risk clinical population.

Keywords: Hippocampus; Magnetic resonance imaging; Neurodevelopment; Very preterm infant; White matter injury.

Fig. 1

Hippocampal segmentations in full-term infant and very preterm infant with brain injury. T2-weighted MRI images demonstrating axial, coronal and sagittal views and 3D volumetric reconstructions of segmented hippocampi bilaterally for a representative individual A) full-term infant and B) very preterm infant with post-hemorrhagic hydrocephalus. Note the gross difference in hippocampal volumes between the control and injured infants. Blue = right and red = left hippocampus.

Fig. 2

Injury categories determined by MRI results. Axial T2-weighted MRI scans demonstrating representative individual infants in each brain injury category. A) Full-term infant; B) very preterm infant without BI, note dolichocephalic shape and decreased folding but otherwise normal anatomy; C) very preterm infant with grade III/IV intraventricular hemorrhage (IVH), note presence of intra- and periventricular hemorrhage; D) very preterm infant with IVH and post-hemorrhagic hydrocephalus (PHH) requiring neurosurgical intervention, note dilated lateral ventricles; and E) very preterm infant with cystic periventricular leukomalacia (cPVL), note cysts surrounding the lateral ventricles. All MRI scans performed at term equivalent postmenstrual age.

Fig. 3

Corrected hippocampal volumes across groups. Plots demonstrating corrected hippocampal volumes for each infant category, including full-term infants (FT), very preterm infants with no to mild brain injury (VPT), very preterm infants with grade III/IV intraventricular hemorrhage (IVH), very preterm infants with IVH and post-hemorrhagic hydrocephalus requiring neurosurgical intervention (PHH) and very preterm infants with cystic periventricular leukomalacia (cPVL). Overall, the PHH group had the smallest hippocampi. Black = left and white = right corrected hippocampal volumes (ratios). Error bars represent one standard deviation.

Fig. 4

Corrected hippocampal volumes decrease as ventricular size increases. Scatter plots demonstrating A) left and B) right corrected hippocampal volumes (cHC; ratios) versus hemisphere-specific fronto-occipital horn ratios (FOHR) for infants grouped by injury category. Fit lines generated using Pearson's correlation. Circle = full-term infants (FT), cross = very preterm infants with no to mild brain injury (VPT) and triangle = very preterm infants with brain injury (BI).

Fig. 5

Relationship between corrected hippocampal volumes and cognitive outcomes. Scatter plots demonstrating relationships between neonatal A) left and B) right corrected hippocampal volumes (cHC; ratios) and Bayley Scales of Infant and Toddler Development, 3rd edition cognitive composite scores at age 2 years for each group. Note that the very preterm infants with brain injury demonstrate strong positive relationships unique to this group. Circle = full-term infants (FT), cross = very preterm infants with no to mild brain injury (VPT) and triangle = very preterm infants with brain injury (BI).