Population Atlas Analysis of Emerging Brain Structural Connections in the Human Fetus

Abstract

Background: A lack of in utero imaging data hampers our understanding of the connections in the human fetal brain. Generalizing observations from postmortem subjects and premature newborns is inaccurate due to technical and biological differences.

Purpose: To evaluate changes in fetal brain structural connectivity between 23 and 35 weeks postconceptional age using a spatiotemporal atlas of diffusion tensor imaging (DTI).

Study type: Retrospective.

Population: Publicly available diffusion atlases, based on 60 healthy women (age 18-45 years) with normal prenatal care, from 23 and 35 weeks of gestation.

Field strength/sequence: 3.0 Tesla/DTI acquired with diffusion-weighted echo planar imaging (EPI).

Assessment: We performed whole-brain fiber tractography from DTI images. The cortical plate of each diffusion atlas was segmented and parcellated into 78 regions derived from the Edinburgh Neonatal Atlas (ENA33). Connectivity matrices were computed, representing normalized fiber connections between nodes. We examined the relationship between global efficiency (GE), local efficiency (LE), small-worldness (SW), nodal efficiency (NE), and betweenness centrality (BC) with gestational age (GA) and with laterality.

Statistical tests: Linear regression was used to analyze changes in GE, LE, NE, and BC throughout gestation, and to assess changes in laterality. The t-tests were used to assess SW. P-values were corrected using Holm-Bonferroni method. A corrected P-value <0.05 was considered statistically significant.

Results: Network analysis revealed a significant weekly increase in GE (5.83%/week, 95% CI 4.32-7.37), LE (5.43%/week, 95% CI 3.63-7.25), and presence of SW across GA. No significant hemisphere differences were found in GE (P = 0.971) or LE (P = 0.458). Increasing GA was significantly associated with increasing NE in 41 nodes, increasing BC in 3 nodes, and decreasing BC in 2 nodes.

Data conclusion: Extensive network development and refinement occur in the second and third trimesters, marked by a rapid increase in global integration and local segregation.

Level of evidence: 3 TECHNICAL EFFICACY: Stage 2.

Keywords: complex network analysis; fetal brain; in utero imaging; structural connectome.

Fig. 1

Fetal brain network visualization at three gestational ages (GA). Colors represent the weighted edge value calculated as the number of fibers connecting two nodes normalized by the inverse of the streamline length. Blue colors represent low edge values, while red colors represent high edge values. Upper pane: Connectivity matrix heatmap. Lower pane: Fetal brain network visualization as a ball-and-stick model (nodes are the balls, and edges are the sticks). Edges with values < 2 have been removed.

Fig. 2

Complex network analysis in the fetal brain. A) Change in whole brain global efficiency with gestational age. B) Change in whole brain local efficiency with gestational age. C) Sigma value at every gestational week; sigma values > 1 signify small-world properties

Fig. 3

Analysis of hemispheric networks. A) Change in each hemisphere’s global efficiency with gestational age. B) Change in each hemisphere’s local efficiency with gestational age. C) Sigma value at every gestational week in each hemisphere; sigma values > 1 signify small-world properties

Fig. 4

Nodal efficiency (NE) is depicted at three gestational ages (GA). Node size represents the NE value at each given age. Nodes with NE positively associated with gestational age are depicted in green

Fig. 5

Betweenness centrality (BC) is depicted at three gestational ages (GA). Node size represents the BC value at each given age. Nodes with BC positively associated with gestational age are depicted in green, and those negatively associated are depicted in red