Aberrant structural and functional connectivity and neurodevelopmental impairment in preterm children

Abstract

Background: Despite advances in antenatal and neonatal care, preterm birth remains a leading cause of neurological disabilities in children. Infants born prematurely, particularly those delivered at the earliest gestational ages, commonly demonstrate increased rates of impairment across multiple neurodevelopmental domains. Indeed, the current literature establishes that preterm birth is a leading risk factor for cerebral palsy, is associated with executive function deficits, increases risk for impaired receptive and expressive language skills, and is linked with higher rates of co-occurring attention deficit hyperactivity disorder, anxiety, and autism spectrum disorders. These same infants also demonstrate elevated rates of aberrant cerebral structural and functional connectivity, with persistent changes evident across advanced magnetic resonance imaging modalities as early as the neonatal period. Emerging findings from cross-sectional and longitudinal investigations increasingly suggest that aberrant connectivity within key functional networks and white matter tracts may underlie the neurodevelopmental impairments common in this population.

Main body: This review begins by highlighting the elevated rates of neurodevelopmental disorders across domains in this clinical population, describes the patterns of aberrant structural and functional connectivity common in prematurely-born infants and children, and then reviews the increasingly established body of literature delineating the relationship between these brain abnormalities and adverse neurodevelopmental outcomes. We also detail important, typically understudied, clinical, and social variables that may influence these relationships among preterm children, including heritability and psychosocial risks.

Conclusion: Future work in this domain should continue to leverage longitudinal evaluations of preterm infants which include both neuroimaging and detailed serial neurodevelopmental assessments to further characterize relationships between imaging measures and impairment, information necessary for advancing our understanding of modifiable risk factors underlying these disorders and best practices for improving neurodevelopmental trajectories in this high-risk clinical population.

Keywords: Functional connectivity; Magnetic resonance imaging; Neurodevelopmental disorders; Prematurity; Structural connectivity.

Fig. 1

Functional connectivity differences between term and very preterm infants. a Left: group mean amygdala resting state-functional connectivity correlation maps for full-term and very preterm infants scanned at term equivalent postmenstrual age; right: z scores demonstrating group differences in connectivity obtained from voxelwise t test. Blue voxels denote areas with greater negative correlations and orange voxels denote areas with greater positive correlations in term infants. Results thresholded using |z| > 2.25 and 53 contiguous voxels achieving whole-brain false-positive rate of 0.05. Adapted with permission from Rogers CE, et al. JAACAP. 2017; 56(2):157-166. b Left: group mean covariance matrices representing multiple canonical RSNs for full-term and very preterm infants at term equivalent postmenstrual age; right: difference between these two results (term minus preterm). Black stars denote cells with between group difference on two-tailed Mann-Whitney U test (p < 0.05; multiple comparisons uncorrected). Adapted with permission from Smyser CD, et al. Cerebral Cortex. 2016; 26(1):322-333. c Functional connections important for differentiating full-term versus very preterm infants using support vector machine-multivariate pattern analysis to analyze data from 244 regions of interest located throughout the brain. Connections stronger in term infants are shown in green; those stronger in very preterm infants are in orange. The caliber of each connection is weighted by the difference magnitude. Adapted with permission from Smyser CD, et al. NeuroImage. 2016; 136:1-9

Fig. 2

Relationship between regional neonatal structural connectivity measures and developmental outcomes in preterm children. a Boxplots of hemispheric asymmetry between neonatal left and right inferior temporal lobe white matter fractional anisotropy in very preterm infants scanned at term-equivalent age and Bayley-III Motor Composite Categories based upon assessments performed at age 2 years, corrected. b Regression plot demonstrating the relationship between fractional anisotropy in the left cingulum bundle at term-equivalent age and competence scores on the Infant Toddler Social Emotional Assessment (ITSEA) tool at age 2 years, corrected. Note the association between more impaired (lower) ITSEA competence scores and higher FA (p = .001). Adapted with permission from Rogers CE, et al. Pediatric Research. 2016; 79(1-1):87–95

Fig. 3

Relationship between neonatal amygdala functional connectivity and social-emotional outcomes in preterm children. Results from whole-brain analysis investigating the relationship between neonatal functional connectivity of left amygdala and internalizing scores on the Infant Toddler Social Emotional Assessment (ITSEA) tool at age 2 years, corrected. Images demonstrate higher total internalizing domain scores were positively correlated with functional connectivity measures between the left amygdala and the medial prefrontal cortex, right anterior insula, and superior frontal cortex. Results thresholded using |z| > 2.25 and 53 contiguous voxels achieving whole-brain false-positive rate of 0.05. Adapted with permission from Rogers CE, et al. JAACAP. 2017; 56(2):157–166