Spatial-Temporal Atlas Of Human Fetal Brain Development During The Early Second Trimester

The fetal brain is substantially different from the neonatal brain in terms of its structure and connectivity. Driven by the ongoing magnetic resonance imaging (MRI) techniques progress, fetal MR imaging has been more and more applied in clinical prenatal diagnosis. Moreover, it also become an essential tool to study fetal brain development and maturation. MRI can provide information both about gross anatomical structures as well as histological microstructures, lamination and sulcation for example. It is essential to understand MR signal changesassociated with maturation, including the appearance and disappearance of transient structures, the underlying histological developmentof thefetal brain as well as the timing of developmentof landmarks in maturation. The availability of post-acquisition morphometric methods and powerful new software tools enable the study of early fetal brain development and maturation. The use of atlases can significantly improve the accuracy and efficiency of automated analysis of brain MRI data. However, fetal brain undergoes more changes in size, shape and structure than at any other time in life, even in every week. A single atlas can’t meet the requirement of different gestational ages. Most of studies have a limited number of subjects, a narrow age range. Therefore, building a spatio-temporal atlas to model the dynamic changes during early brain development becomes very necessary.The second trimester ranges from14th week of pregnancy to27th week, and is considered to be a specific window of vulnerability for the fetus. During this period, the enormous neurogenesis and neuronal migration are happening, so relatively minor disruptions may significantly alter the structure and function of the maturing brain. Studies of normal and pathological brain development during this period are critical for our understanding of the etiology and the associations between neurological traits and different environmental phenotypes. In clinical settings, fetal MRI is usually performed after the19th gestational week. Therefore, most fetal MRI studies, construction of spatial-temporal brain atlases,3D reconstruction, tissue segmentation etc. for example, are focused on the later period of the second trimester and afterwards. Fetal atlases covering age-range of the early second trimester of pregnancy are currently missing in the scientific community.Fetal MRI in vivo has many restrictions due to the smaller brain-size, sequence selection, and frequent fetal generic movements. It is difficult to obtain high-quality images with detailed local anatomy. However, postmortem fetal specimen offer advantages by allowing the use of high-field strength magnets, smaller field of view, reduced slice thickness, and increased acquisition time. Some pioneering studies have demonstrated the correspondences between histological structures and MRI bioimaging markers. This study aims to provide fetal brain atlases for quantitative assessment of morphometric brain changes, yield clues to the underlying brain maturation patterns and mechanisms during the early second trimester, and provide references for clinical diagnosis during the early fetal brain development.Part1:Establishment of fetal brain atlases during the early second trimesterObjective:The use of spatiotemporal atlases can significantly improve the results and efficiency of automated analysis of fetal brain MRI data. The current study aims to establish age-specific fetal brain atlases of the early second trimester (15-22gestational weeks)Materials and Methods:The thirty-four postmortem fetal specimens of15-22weeks GW were collected and performed in a7.0T Micro-MRI. Both the data conversion and bias field correction were implemented as Pipeline workflows developed by Laboratory of Neuroimaging of UCLA. Manual removal of the non-brain tissue was performed using BrainSuite software. For each cortex,4complementary global shape metrics were computed using LONI ShapeTools pipeline library-volume, surface area, shape index and curvedness. The script buildtemplateparallel.sh of Advanced Normalization Tools (ANTs) developed by University of Pennsylvania was run in each week to build the average template of each week. Three-Dimension surface reconstruction of these templates were performed by BrainSuite. The general template was built from these weekly templates.Results:From15to22gestational weeks, growth trajectories of brain area and volume is fitted well by linear regression model. The whole brain increased in volume by approximately4-fold and about2.5-fold in area. To reduce the bias effects of different demographic distributions of different numbers within each week, we built the templates each week first. After3D surface reconstruction of these templates, we found that the15th week still has some trails of neural folding in the early stages. The brain surface of22nd week still looks smooth, but the whole brain’s general shape looks more mature. The aggregated general template was then built based on these weekly templates. Four layers of lamination structures are displayed, from outer to inner, these layers are: cortical plate, subplate zone, intermediate zone, ventricular zone. The composed parts of basal ganglia could also be distinguished.Conclusion:Our study first established the spatial-temporal atlas of the early second trimester. And we also obtained the general developmental trajectories of the early fetal brain development. These atlases based on the high-field MRI data provide good resolution and contrast, which will enable to characterize the dynamic anatomical changes of fetal brain development. Part2:Development of lamination structure and subcortexObjective:Lamination structure is one of the most important characters of fetal brain. This study aims to make the use of transform values during the atlas building to analyze the age-specific changes in the patterns of lamination and subcortex structures from15to22gestational weeks.Materials and methods:Each subject’s brain was registered to the corresponding template built at the first research part. Using ANTS, the affine and warp transform files of each subject computed during the registration were composed to one deformation file, and then calculated to be Jacobian. Using FSLStats module in LONI Pipeline, we obtained the statistics of Jacobian field.Regional structural differences of deformation fields were represented as (Tensor-based morphometry) TBM maps. The general linear model was used to study the associations between localized quantitative deformation of different brain structures and gestational weeks. The computational libraries of the Statistics Online Computational Resources (SOCR) wrapped as Pipeline modules were used for computing shape-based statistics.Results:Nearly the entire lamination grows significantly, except for parts of ventricular zone and intermediate zone in the frontal and occipital lobes. Compared with other layers, the subplate zone show more significant correlation with GW and a bigger growth rate. Regional developmental differences could be found within the subplate zone. However, the ventricular zone (including ganglionic eminence) does not show significant changes. Lateral ventricles in the frontal and parietal lobes show negative correlation and growth rate, which implies local volume contractions. Thalamus with a higher correlation than basal ganglia. But basal ganglia has a bigger growth rate.Conclusion:Based on population-base statistics, this study first analyze the development trajectories of lamination structures during the early second trimester. The results showed the subplate zone shows most obvious growth pattern, and is the predominant cause of the changes in the lamination pattern of the cerebral wall. Part3:Prior and atlas-based segmentation of the laminar organizationObjective:This study aims to segment the laminar organization bycombining manual and automatic methods with prior and atlas-based segmentation, to construct spatiotemporal atlases of the fetal brain with temporal models of tissue probability of laminar layers.Materials and methods:ITK-SNAP tool was chosen to do the manual segmentation. Laminar organization of cerebral wall in the overall atlas, which represents the structures of fetal brain between15and22GW, was segmented for four layers.From pial surface to ventricular, they are: cortical plate (CP), subplate zone (SP), intermediate zone (IZ), ventricular zone (VZ)-After manually segmented label image was finished at the overall atlas, segmented image was transformed to the segmentation information of each week’s atlas. This process is realized by use of opposite direction of WarpImageMultiTransform in ANTS. Segmentation is realized byAtroposin the ANTS, based on the prior information of inversewarped segmentation.We then calculated volumes of the segmented structures, as well as the statistics of the image intensity for each structure using ITK-SNAResults:The probabilistic maps of laminar layers are created and we create a set of accurate delineations of four layers including cortical plate, subplate zone, intermediate zone and ventricular zone.3D mesh surface and quantitative measurements of each layer are displayed and analyzed, which allow us to capture the appearance, disappearance and spatial variation of brain structures over time. Thevolumes of every layer grow steadily with increasing ages, and subplate zone shows a more significant growth characteristic.The mean intensity and standard deviation decrease with GW imply that the composition of each layer is becoming more and more uniform.Conclusion:Experimental results indicate that subplate zone shows most obvious growth pattern and using manual segmentation as prior can correctly capture growth-related changes in the fetal cerebral wall and provide improvement in accuracy of atlas-based tissue segmentation.Laminar organization grows toward mature during the period we study. Part4:Sylvian fissure development and growth directionObjective:This study aims to characterize the developmental trajectory of Sylvian fissure, the earliest sulcus during the early brain development. And we also explored the mechanisms of sulcal formation during development. Besides, by analyzing changes of cortical surface deformation during development, we explored the global and different lobes growth pattern.Materials and methods:We used the fast marching algorithm to compute the signed distance function, and then converted the triangular mesh representation to implicit representations of surfaces in replacement of regulargrid. Then we computed the mean curvature on the surface on Euclidean space to observe the folding process of Sylvian fissure. We performed surface registration of the template cortical model to each individual cortical surface using a diffeomorphic algorithm. Then local shape analysis (LSA) pipeline workflow was used to obtain local shape metrics (displacement-field, radial-distance), per vertex in the triangulated surface representations. Using SOCR, these two local shape measures were used as covariates with gestational week to generate brain maps at each cortical location, and captured local expansions or contractions of the developing cortical surface.Results:Development process of brain surface was demonstrated by mean curvature. And the Sylvian fissure is widely open, obtuse and shallow in the early stage. Subsequently, it becomes narrow, deeper and longer, and its mean curvature increased continuously. The cortex around the Sylvian fissure, especially on the frontal and parietal lobes, has a higher growth rate and more significant correlation. The most significant changes in displacement-field were observed in the anterior region of temporal lobe. For the entire cortical surface, there are more vertices with positive correlation values in both the anterior and posterior areas, but more negative ones superiorly and inferiorly. For the radial-distance metric, there are only positive correlation values. However, vertices in the anterior surface of the frontal lobe, the temporal lobes and the posterior surface of the occipital lobe have higher growth rate and more significant correlation.Conclusion:The faster growth of the cortex contributes to the folding process of the Sylvian fissure. Every vertex on the surface undergoes radially expanding from15to22GW. The brain shape extends in both the anterior and posterior directions during this period, In particular the development of the frontal, temporal and occipital lobes.