In overview, we detected volumetric patterns of significantly (p < 0.05, corrected) slower or faster linear growth than the overall cerebral growth rate as determined from voxelwise and surface-based analyses. Reported local rates are percent volume change per week relative to the average cerebral growth rate of 17% per week (). For example at a particular voxel or vertex, −6% means that this location grew 6% per week less than the average weekly rate of 17%, or an absolute rate of approximately 11% per week. Voxelwise results are presented in order of increasing depth of the brain: cortical plate, remaining fetal brain tissue zones and subcortical nuclei (NCP), and ventricles. Significant changes in volume are predominantly bilateral unless noted otherwise. T statistic maps displayed in each orthogonal plane and minimum and maximum intensity projections are included in Supplemental Materials.
In this TBM study, folding of the cortical plate would appear as a greater expansion rate at sulcal fundi because the tissue is being warped away from the corresponding voxel on the average brain. Therefore our interpretation of faster growth in the cortical plate at anticipated sulcal sites reflect the additional in-folding of the sulci relative to the outer skull boundary. Without additional image contrasts that provide cortical landmarks (e.g., DTI) to define corresponding regions of cortex at different developmental ages, these maps cannot directly examine differences in growth rate between gyral crests and sulcal valleys as histological studies may be able (Bystron et al., 2008
; Hilgetag and Barbas, 2006
For the voxelwise analysis, growth rate maps showing regions of significantly increased or decreased growth (compared to the overall growth) are overlaid on the spatially normalized average MRI () and displayed using the RView software (http://rview.colinstudholme.net
). T-value surface maps computed from the analysis of the CP surfaces are used to indicate differential growth patterns on the CP with contours delineating regions of statistically significant local variations in growth rates (). Mean relative growth rates are reported in and for regions that exhibit significantly greater growth rate than average cerebral growth rate. Differences in relative growth rates between less and more mature groups are studied by comparing their individual regression analyses (, ). Lastly, we tested for local volume differences across hemispheres over the full age range and the age subgroups (, ).
Figure 4 Local tissue growth rate patterns relative to cerebral growth rate, overlaid on the average brain. Color scale represents growth rate per week for each voxel. Figure panels display axial sections from superior to inferior at 5 mm intervals. Growth rate (more ...)
Figure 5 Cortical growth rate patterns. (a) Dorsal and (b) lateral views of T statistic map of the model of CP volume increases. White contours indicate regions that are statistically significantly different from the cerebral growth rate after multiple comparisons (more ...)
Average regional growth rates (relative to cerebral growth rate) for the most significant regions. NCP, not cortical plate
Figure 6 Regional analysis of growth rate changes for bilateral ROIs with volume ≥ 0.2 cm3. Mean Jacobian determinant calculated for each significant ROI, for all subjects mapped against age of the subject is shown in (a) to (e). Each panel shows the best (more ...)
Surface rendering of average shape of the inner CP for (a) 20 to 23 weeks gestational age (GA) and (b) 24 to 28 weeks GA. The progression of folding is clearly visible, with primary sulci discernible on the average inner CP surface in (b).
Figure 8 Maps showing the changes in the relative linear growth pattern over time between the more and less mature groups. T statistic map of CP growth rate relative to overall cerebral brain growth, overlaid on average the CP surface for the less (a) and more (more ...)
Figure 9 T statistic maps of significant (p < 0.05, corrected) local volumetric asymmetries present from 20 to 28 weeks GA, in which warm colors indicate right hemisphere greater than left and cool colors represent left greater than right. T-values are (more ...)
Figure 10 Cross-sectional images of the CP mask and symmetrical contour of the average brains from (a) 20 to 23 weeks GA and (b) 24 to 28 weeks GA shown in the axial (left) and coronal (right) planes. The asymmetry in the peri-Sylvian region is clearly visible (more ...)
Local relative growth patterns
The deformation tensor model localized to the cortical plate is sensitive to focal changes in both cortical thickness and area. Local growth in the cortical plate was either similar to or significantly greater than the overall cerebral rate (). Quantitatively, from the regional analysis, the local relative growth rates varied in that the greatest deviations were up to twice the global rate (, ). Similar patterns in the cortical plate were found in the voxelwise and surface analyses though larger regions of significant change were detected by the models specifically constrained to the surface (). The most rapid growth in the cortical plate occurred along the midline surface of the frontal and parietal lobes (). Posterior to the central sulcus, the dorsal and lateral cortical plate expanded faster than the overall cerebral rate (; ). Specifically, increased growth was apparent over most of the insula and frontal, parietal and temporal opercula ().
Other areas of significantly greater growth were found bilaterally at emerging sulci: central (; ; ), circular (; ), and cingulate (). From the quantitative regional analysis, the central and cingulate sulci expanded at the greatest relative rate compared to other locations in the cortical plate (). However, the regional growth rate along these sulci were better fit by exponential curves, rather than a constant linear rate (), which indicates an acceleration of growth in these regions. To a lesser degree, the lateral orbital (), superior temporal (), right parieto-occipital (), and right calcarine () sulci grew at increased rates.
Fetal brain tissue zones and subcortical nuclei
In large uniform regions of the fetal brain tissue zones (such as deep within the cerebral mantle), the available contrast of T2w MRI (and the derived NCP segmentation) limits our ability to localize volume changes to specific tissue zones. As a result, TBM studies of patterns of tissue expansion or contraction occurring within these regions must be interpreted with care. However, by using an optimally smooth regularization of the deformation fields, the observed volume increases or decreases in these cases correspond to regions where surrounding tissue boundaries are consistently moving away or toward the center of growth respectively.
Relative growth rates in the NCP varied spatially. The greatest regional growth rates, around 11% greater than overall brain growth, were located in the anterior frontal and temporal lobes and the opercula (). Importantly, increased relative growth was found in areas associated with gyrification: operculum (), superior temporal gyrus (), pre- and post-central gyri (), parietal lobules () and ventromedial occipital lobe (). In contrast to subplate and intermediate zone deep to the developing operculum, regions deep to the insula expand at a slower rate (). The dorsomedial aspect of the subplate and intermediate zone in the frontal and the parietal lobes () and the anterior frontal cerebral mantle () grew faster than the overall cerebral rate. Near 20 weeks GA, the relative size of these cerebral mantle areas to the average brain was similar, as shown by the growth curve intercept (calculated from regional analyses) in . Further calculation of the regional mean rates show that these are growing linearly with age ().
Some regions of subcortical nuclei displayed significantly greater than cerebral growth rates. The ventral part of the basal ganglia showed elevated relative growth rates () as well a region localized to the anterior thalamus (). The hippocampus showed accelerated growth in the tail bilaterally and in the right anterior part (). Reduced growth rates were localized to the basal forebrain ().
Decreased relative growth rates were observed in the NCP, close to the NCP-VENT boundary, corresponding to the germinal matrix bilaterally in frontal (), parietal (), and occipital () lobes. In the frontal lobe, only the germinal matrix surrounding the horns of the lateral ventricles had a lower growth rate. In the parietal lobe, the germinal matrix around the lateral ventricles, and not the subcortical nuclei showed significantly lower relative growth rates. No areas of the germinal matrix exhibited greater than cerebral growth rates.
The boundary of the ventricles shared with the cerebral mantle showed decreased relative growth rate (). The ventricles did not have any areas of relatively greater growth rate than the whole cerebrum.
Relative growth patterns before and after 24 weeks GA
The mean NCP surfaces of the average shape of the less and more mature groups are shown in and demonstrate the increased volume and development of cortical folds with age in the two groups. In the TBM analysis, as a consequence of smaller group sizes and conservative multiple comparisons correction, fewer voxels reached significance in the analysis within the age groups and the patterns exhibited less similarity in both hemispheres compared to the results from the full age range (). Despite this, the patterns in the relative growth rate maps of the more mature group were similar to that of the full age range (). In the latter age group, increased relative growth rates were localized to the central, cingulate and superior temporal sulci and dorsal parietal and occipital lobes. Relative to the average growth rate from 24 to 28 weeks GA, the opercula had a lower growth rate, which was unlike the broader age range.
The pattern of growth in the less mature group qualitatively matched that of the full age range, in that reduced relative growth rates were present in much of the dorsal frontal lobe (). In contrast to the more mature group, the posterior operculum and insula grew at a slightly faster rate in the less mature group, which is also represented in the full age range.
Hemispheric volume asymmetry
In some regions of accelerated growth, the volume was not bilaterally symmetrical. Specifically, the opercula showed a distinct asymmetry in which the left posterior fronto-parietal operculum was larger than the right and the right posterior temporal operculum was larger than the left (). As shown by asymmetry analysis of the less and more mature age groups, the location of significant asymmetry shifted posteriorly with age (). The difference in the local volume is illustrated in , in which the original and symmetrical average cortical plate are overlaid. The frontal and postcentral dorsomedial cerebral mantle, including cortical plate, was larger in the right hemisphere () and did not include the frontal pole. This pattern was also found when the more mature group was analyzed alone (). Though in the less mature group, right great than left asymmetry was primarily localized to the presumptive precentral gyrus ().
A small area of the left parahippocampal cerebral mantle was larger on the left compared to the right and this asymmetry was present in the age subgroups. In the analysis of the entire age range, the ventromedial cerebral mantle of the occipital pole was larger in the left hemisphere, but this was not detected in either subgroup. In addition, an area of the caudate body was larger in the right hemisphere when the whole group was analyzed, but not in either subgroup. In a ventrolateral part of the cerebral mantle of the posterior temporal lobe, there was a localized region that was larger on the left hemisphere, though this did not correspond to a distinct anatomical location. In the less mature group only, the tail of the hippocampus was larger in the left hemisphere. There were not any regions of significant asymmetry found in the more mature group alone.