Longitudinal analysis of neural network development in preterm infants

Abstract

Application of resting state functional connectivity magnetic resonance imaging (fcMRI) to the study of prematurely born infants enables assessment of the earliest forms of cerebral connectivity and characterization of its early development in the human brain. We obtained 90 longitudinal fcMRI data sets from a cohort of preterm infants aged from 26 weeks postmenstrual age (PMA) through term equivalent age at PMA-specific time points. Utilizing seed-based correlation analysis, we identified resting state networks involving varied cortical regions, the thalamus, and cerebellum. Identified networks demonstrated a regionally variable age-specific pattern of development, with more mature forms consisting of localized interhemispheric connections between homotopic counterparts. Anatomical distance was found to play a critical role in the rate of connection development. Prominent differences were noted between networks identified in term control versus premature infants at term equivalent, including in the thalamocortical connections critical for neurodevelopment. Putative precursors of the default mode network were detected in term control infants but were not identified in preterm infants, including those at term equivalent. Identified patterns of network maturation reflect the intricate relationship of structural and functional processes present throughout this important developmental period and are consistent with prior investigations of neurodevelopment in this population.

Figure 1.

Longitudinal neural network development in preterm infants. Average fcMRI correlation maps corresponding to varied seed locations. The images are organized in columns corresponding to PMA at time of imaging. The illustrated quantity is the group mean Fisher z-transformed correlation coefficient (threshold value = 0.3) overlaid on the gestational age–specific atlas (Supplementary Figs 1 and 2). Each row shows the axial slice at the level of the seed region. Networks in preterm infants demonstrated limited intrahemispheric connectivity. Note age-dependent network maturation. Included are networks identified utilizing seeds located in the (A) motor cortex—leg (Z = 63), (B) motor cortex—hand (Z = 48), (C) motor cortex—face (Z = 39), (D) posterior cingulate cortex (PCC) (Z = 15), (E) anterior cingulate cortex (ACC) (Z = 15), (F) occipital cortex (Z = −3), (G) medial prefrontal cortex (MPFC) (Z = −3), (H) lateral prefrontal cortex (LPFC) (Z = −3), (I) temporal cortex (Z = 9), (J) thalamus (Z = 9), and (K) cerebellum (Z = −45). The right side of the image corresponds to the right side of the brain. The number of subjects contributing to each PMA group is 27 weeks, n = 10; 30 weeks, n = 16; 34 weeks, n = 36; 38 weeks, n = 28; and term control infants, n = 10 (see also Table 1 and Supplementary Table 1).

Figure 2.

Functional connections demonstrate characteristic patterns of maturation based on location. Scatter plots demonstrating relationship between correlation values for regions of interest and PMA. Linear regression performed on result with correlation coefficient and measure of significance included. (A) Right and left anterior cingulate cortex (ACC) demonstrates significant interhemispheric connectivity between homotopic counterparts from earliest acquisition point with limited variability with advancing gestational age. Image is representative of those produced using medial seed locations. (B) Right and left sensorimotor (SM) cortex demonstrates statistically significant increase in interhemispheric connectivity between homotopic counterparts with advancing gestational age. Image is representative of those produced using lateral seed locations. (C) Right and left temporal cortex demonstrates limited interhemispheric connectivity between homotopic counterparts throughout early development. (D) Right medial prefrontal cortex (MPFC) and right posterior cingulate cortex (PCC) demonstrate limited connectivity between regions of interest in preterm infants (solid black circles), including those at term equivalent PMA. A subset of term control infants (blue Xs) demonstrate increased connectivity between these regions.

Figure 3.

Significant differences in functional connectivity between term equivalent and term control infants using seed region located in the thalamus. (A) Average fcMRI correlation maps generated using a right thalamic seed demonstrating qualitative differences in functional connections between preterm infants at term equivalent PMA (n = 28) and term control infants (n = 10). Included are sensorimotor cortex—leg (Z = 54/51/48), thalamic (Z = 12/9/6), and brainstem (Z = −15/−18/−21) regions. The correlation map generated for the term equivalent infants demonstrates limited functional connections superiorly to the sensorimotor cortex and inferiorly to the brainstem and cerebellum in comparison with those identified for term control infants. z(r) threshold 0.3 used. (B) These patterns are confirmed through direct comparison between these populations via voxel-wise t-test with subsequent conversion of t statistic values to equiprobable Z scores (random-effects analysis). Connections between the thalamus and sensorimotor cortex and brainstem and cerebellum are significantly stronger in term control infants. Z score threshold 1.65 (corresponding to P < 0.05) used. The right side of the image corresponds to the right side of the brain.

Figure 4.

Results for infants with complete longitudinal data sets are consistent with those obtained for larger group analysis. Average fcMRI correlation maps generated using sensorimotor cortex—leg (Z = 63), sensorimotor cortex—hand (Z = 48), anterior cingulate cortex (ACC) (Z = 15), and occipital cortex (Z = −3) seed locations demonstrating longitudinal neural network development in 5 subjects studied at final 3 acquisition times. Results are similar to those from larger group analysis, demonstrating a comparable age-dependent pattern of development with increasing strength and organization with advancing gestational age. This demonstrates that correlation maps obtained in the larger group analysis were not biased by inclusion of specific infant populations. z(r) threshold 0.3 used. The right side of the image corresponds to the right side of the brain.

Figure 5.

Default mode network precursors identified in term infants. Average fcMRI maps demonstrating putative default mode network precursors, including connections between the medial prefrontal and posterior cingulate cortices (arrows), identified in term control infants (n = 10) utilizing right medial prefrontal cortex (MPFC) seed location (Z = 21, X = 1). Further quantitative analysis demonstrates that these images likely reflect prominent anterior–posterior connectivity in a subset of these infants, with a number of infants within the group continuing to show limited connection strength between these regions. Comparable findings were not identified in preterm infants, including those at term equivalent PMA. z(r) threshold 0.3 used. The right side of the image corresponds to the right side of the brain.