The Developing Human Connectome Project: typical and disrupted perinatal functional connectivity

Abstract

The Developing Human Connectome Project is an Open Science project that provides the first large sample of neonatal functional MRI data with high temporal and spatial resolution. These data enable mapping of intrinsic functional connectivity between spatially distributed brain regions under normal and adverse perinatal circumstances, offering a framework to study the ontogeny of large-scale brain organization in humans. Here, we characterize in unprecedented detail the maturation and integrity of resting state networks (RSNs) at term-equivalent age in 337 infants (including 65 born preterm). First, we applied group independent component analysis to define 11 RSNs in term-born infants scanned at 43.5-44.5 weeks postmenstrual age (PMA). Adult-like topography was observed in RSNs encompassing primary sensorimotor, visual and auditory cortices. Among six higher-order, association RSNs, analogues of the adult networks for language and ocular control were identified, but a complete default mode network precursor was not. Next, we regressed the subject-level datasets from an independent cohort of infants scanned at 37-43.5 weeks PMA against the group-level RSNs to test for the effects of age, sex and preterm birth. Brain mapping in term-born infants revealed areas of positive association with age across four of six association RSNs, indicating active maturation in functional connectivity from 37 to 43.5 weeks PMA. Female infants showed increased connectivity in inferotemporal regions of the visual association network. Preterm birth was associated with striking impairments of functional connectivity across all RSNs in a dose-dependent manner; conversely, connectivity of the superior parietal lobules within the lateral motor network was abnormally increased in preterm infants, suggesting a possible mechanism for specific difficulties such as developmental coordination disorder, which occur frequently in preterm children. Overall, we found a robust, modular, symmetrical functional brain organization at normal term age. A complete set of adult-equivalent primary RSNs is already instated, alongside emerging connectivity in immature association RSNs, consistent with a primary-to-higher order ontogenetic sequence of brain development. The early developmental disruption imposed by preterm birth is associated with extensive alterations in functional connectivity.

Keywords: brain development; functional connectivity; neonatology; neuroanatomy; resting-state connectivity.

Figure 1

Resting state networks identified by group independent component analysis. Spontaneous BOLD activity patterns (RSNs) derived from group ICA in 24 term-born infants scanned at 43.5–44.5 weeks PMA. Panels: Example axial, coronal, and sagittal slices for meaningful spatial patterns in primary (A) and association (C) RSNs, thresholded at Z > 3 and overlaid on a T₁ structural template, displayed in radiological convention. Centre: Functional parcellation of the brain using a ‘winner-takes-all’ approach based on the RSNs from group ICA. RSNs were spatially smoothed and thresholded at Z > 1 prior to determination of the ‘winning’ RSN at each voxel. The resulting volume was projected to the midthickness cortical surface using enclosed (nearest neighbour) volume-to-surface mapping, here displayed on the pial surface of an individual subject scanned at 42 weeks PMA and viewed from the dorsal (B) and left lateral (D) aspects.

Figure 2

Changes in network shape with increasing age at scan. Brain regions showing increasing functional connectivity with older PMA at scan in term-born infants scanned at 37–43.5 weeks PMA. Example sagittal, coronal, and axial slices for meaningful spatial patterns in four RSNs are shown, overlaid on a T₁ structural template and displayed in radiological convention. T-statistic maps were thresholded at P < 0.025 (FWE corrected). White lines represent the outlines of the group ICA RSNs, thresholded at Z > 3.

Figure 3

Weekly maturation in functional network structure at term-equivalent age. Group-average t-statistic maps of functional connectivity in term-born infants scanned at 37.5–42.5 weeks PMA, grouped into weekly bins by PMA at scan. Within each bin 20 subjects with the lowest postnatal age at time of scan were selected. Example axial slices for meaningful spatial patterns in primary (A) and association (B) RSNs are shown, overlaid on a T₁ structural template and displayed in radiological convention. Results were thresholded at P < 0.05 (FWE corrected).

Figure 4

Relationship between postmenstrual age at scan and core network strength. Relationship between the residuals (after correcting for sex and motion) for PMA at scan and core network strength in term-born infants scanned at 37–43.5 weeks PMA. Core network strength was defined as the mean β-parameter value in each subject’s RSN-specific spatial map after masking by the corresponding group-ICA network template thresholded at Z > 3. Partial Spearman’s correlation coefficients and associated P-values are displayed for the three RSNs significant at P < 0.025. Example axial, coronal and sagittal slices for meaningful spatial patterns in the corresponding group-ICA network templates are shown for reference.

Figure 5

Increased functional connectivity in the visual association network in female infants. Brain regions showing increased functional connectivity within the visual association RSN in female infants. Example axial, sagittal and coronal slices for meaningful spatial patterns are shown, overlaid on a T₁ structural template and displayed in radiological convention. T-statistic maps were thresholded at P < 0.025 (FWE corrected). White lines represent the outline of the group-ICA visual association network, thresholded at Z > 3.

Figure 6

Effect of preterm birth on functional connectivity. Group differences in functional connectivity between term and preterm-born infants scanned at 37–43.5 weeks PMA. Coloured t-statistic maps thresholded at P < 0.025 (FWE corrected) show brain regions with reduced (blue) or increased (red-yellow) connectivity in preterm-born infants. Example sagittal, coronal, and axial slices for meaningful spatial patterns within each RSN are shown, overlaid on a T₁ structural template and displayed in radiological convention. White lines represent the outlines of the group-ICA RSNs, thresholded at Z > 3. Box plots show group differences in core network strength after regressing out PMA at scan, sex and motion. Core network strength was defined as the mean β-parameter value in each subject’s RSN-specific spatial map after masking by the corresponding group-ICA network template thresholded at Z > 3. P-values relate to the term versus preterm group contrast in a GLM in which core network strength was the dependent variable and PMA at scan, sex and motion were controlled for as nuisance covariates.