| The human hippocampal formation, one of the critical structures in the limbic system, is closely related to learning, memory, and emotion functions. The abnormalities of the hippocampal formation were connected with many congenital cerebral malformations such as lissencephaly, holoprosencephaly and agenesis of the corpus callosum. It is also reflected in many neurological and neuropsychiatric disorders, such as depression, epilepsy, Parkinson’s disease, schizophrenia, and Alzheimer’s disease.Development of the human fetal hippocampal formation has been a subject of increasing interest. The main reason is that hippocampal injury or deviation of the hippocampal formation from its normal development trajectory, such as smaller hippocampal volume, unfolded hippocampal fissure, may be a contributor to the neurodevelopmental burden of affected individuals. The human HF comprises a considerable number of complex substructures, including the dentate gyrus, the Cornu Ammonis, the subiculum, and the associated white matter tracts, such as the fimbria and the alveus. It is therefore difficult to observe small volumetric or shape changes and changes that occur within the substructure because of limited resolution of the images obtained with 1.5T or 3.0T MR in vivo. In addition, in utero MRI is susceptible to frequent fetal movement and pulsatile motion from maternal arteries.Histological studies showed that the prenatal development of hippocampal formation was a progressive rotation process. The hippocampal primordium firstly arises at the dorsal part of the lamina terminalis and can be identified histologically as early as in the 9th GW. The dentate gyrus and the Cornu Ammonis gradually grew and folded into the temporal lobe, together with the gradually closing hippocampal fissure. By 18 to 20 weeks of gestation, the structure of the fetal hippocampal formation has been similar to that of the adult hippocampal formation. However, to date there are no quantitative studies on fetal hippocampal development.The asymmetry of the hippocampal formation is also a concern point. Adolescent and adult studies show that the hippocampal formation is asymmetric, with the right hippocampal formation being larger than the left. Full term infants and premature infants study also found the right side asymmetry of hippocampal formation. Additionally, studies of fetal hippocampal formation indicated that hippocampal fissure show hemispheric difference, with right hippocampal fissure folding earlier than that in the left. This indicated that the right hippocampal formation develops faster than the left. However, a volumetric study of the fetal hippocampal formation found no asymmetry, which may be related to the low resolution of the MR image in utero and the definition of the boundaries of the hippocampal formation is not clear enough. It is therefore hard to determine when the asymmetry of the fetal hippocampal formation in utero arise, as well as is developmental status in the second trimester, which is worth to do further exploration.The second trimester is the stage when the fetal cerebral hemisphere and internal structures grow vitally. The cerebral cortex folds quickly and its volume increases rapidly. The second trimester is also one period during which the laminar organization of the cell layers and the migration of neurons happen, which may lead to developmental related disease and deformity in the clinical diagnosis. It is obvious that the hippocampal formation, which belongs to the limbic system, also changes prominently in this stage. The developmental status of the fetal hippocampal formation in the second trimester, as well as its hemispheric differences may be more evident, and related studies may have a greater clinical value.In this study, we recruited fetal specimens in hospitals of Shandong Province. With the help of 7.0T high-field MRI scanning, observation and segmentation of the hippocampus structure were conducted. Using volume and shape analysis, normal development of the fetal hippocampal formation during early second trimester and its hemispheric differences was clarified. A dynamic 4D template of the developing fetal hippocampal formation was constructed using Advanced Normalization Tools (ANTs) based on image intensity. The results of this study can provide a reference for further research related to the hippocampal formation, as well as for the clinical diagnose.Part 1:Observation and segmentation of the developing fetal hippocampal formation during second trimester.ObjectivesDevelopment of the hippocampal formation has been a subject of increasing interest, especially for the fetal hippocampal formation. This study aims to use the 7.0T MRI of fetal specimen to observe the developing fetal hippocampal formation and manually segment the fetal hippocampal formation referenced by adult hippocampal segmentation protocol and histological atlas. Accurate segmentation of fetal hippocampal formation was conducted and corresponding segmentation protocol was generated.Materials and methods41 specimens range from 14-22 gestational weeks (GW) were collected from hospitals in Shandong Province.7.0T MR scanning was performed in Department of Radiology, Zhong Da Hospital, Southeast University School of Clinical Medicine (Jiangsu Provincial Key Laboratory of Molecular and Functional Imaging). Observation and segmentation of the fetal hippocampal formatting were conducted using e-Film and Amira software.ResultsOverall development of the hippocampal formation from 14 to 22 GW can be clearly demonstrated using 7.0T high-resolution MR images. The widely opened hippocampal fissure was observed at about 14 GW. At 16-19 GW, the gradually closing hippocampal fissure and the germinal matrix can be clearly characterized, as well as the tri-laminar appearance of the hippocampal formation. By the 20th week, the hippocampal formation has been similar to that of the adult hippocampal formation. We segment the fetal hippocampal formation mainly in the axial plane, referenced by the sagittal and coronal planes and build an accurate and consistent segmentation protocol for fetal hippocampal formation.Conclusions7.0T high field MR can clearly show the development of hippocampal formation in the second trimester. The hippocampal formation is one of the earliest developed regions of the fetal brain. The segmentation protocol generated in this study can be used as a reference for the further hippocampal studies.Part 2:Volume analysis of the developing fetal hippocampal formation during second trimester.ObjectivesAt present, researches on the hippocampal formation are mainly focused on the observation. Quantitative analysis, especially for the volume analysis, can be more intuitive to observe the development of fetal hippocampal formation. In this study, 7.0T MR images were acquired and manually segmentation of the fetal hippocampal formation was conducted. Growth trend and hemispheric difference of hippocampal formation were quantitatively calculated.Materials and methods41 specimens of 14-22 GW were used to segment the hippocampal formation with the help of Amira software. The volume, surface area, curvature and other quantitative information of hippocampal masks were calculated on the MATLAB platform. Using the Polyfit method, developmental trends of the hippocampal formation were plotted. Hemispheric differences of the fetal hippocampal formation were calculated using T test.ResultsThe absolute volume of both the left and right hippocampal formation increased linearly with the increasing gestational age weeks. The growth rate decreased slightly after the 18th week. The relative volume of the hippocampal formation showed an inverted U-shape trend. From 14 to 17 GW, the growth increased slowly, followed by a rapid decline. The volume of hippocampal formation was hemispheric, with the right hippocampal formation being larger than the left (t (40)=5.813, p<0.05).ConclusionsHemispheric differences of the developing fetal hippocampal formation were observed, which may be related to different functions. In addition, the inverted U-shaped trend relative volume developmental pattern of hippocampal formation indicated that the hippocampal formation might develop priority, compared with other brain regions. Our research can provide a reference for the quantitative analysis of future hippocampal studies.Part 3:Shape analysis of the developing fetal hippocampal formation during second trimester.ObjectiveVolume analysis is a relatively intuitive method to observe the development of the hippocampal formation as a whole. However, sub-regional changes of the hippocampal formation are hard to achieve just using conventional volume analysis method. Therefore, this study aims to use 7.0T post-mortem MRI, combined with the shape analysis method, to observe morphological changes of fetal hippocampal formation in the second trimester and compare its hemispheric differences.Materials and methods41 specimens of 14-22 GW were recruited to conduct 7.0T MR scanning in Department of Radiology, Zhong Da Hospital, Southeast University School of Clinical Medicine (Jiangsu Provincial Key Laboratory of Molecular and Functional Imaging). Using shape analysis method in Laboratory of Neuro Imaging (LONI), surface meshes (points and lines) of the hippocampal masks were obtained. All subjects were re-sampled to have 1000 grid point. Euclidean distance of each grid point to the hippocampal center was calculated. Regression analysis was used to calculate morphological changes of hippocampal formation and its hemispheric differences.ResultsBoth the right and left hippocampal formation showed a rapid growth. For the left hippocampal formation, the degree of increase for superior and inferior regions of the hippocampal body was lower than other regions. Part of the hippocampal head adjacent to the amygdala (AG), the medial part of the hippocampal body (approximate subiculum), and the posterior part of the hippocampal tail adjacent to the splenium of the corpus callosum also had a lower rate of increase. The anterior part of the hippocampal head, and the medial (approximate dentate gyrus) and lateral regions of the whole HF, on the other hand, increased faster than other regions.For the right hippocampal formation, the rates of increase for superior and inferior regions of the hippocampal head and body, and medial regions of the hippocampal body were lower than other regions. Part of the hippocampal head adjacent to the amygdala and the posterior part of the hippocampal tail adjacent to the splenium of the corpus callosum also had a lower rate of increase. In contrast, the anterior and most medial parts of the hippocampal head and the lateral regions of the whole HF increased faster than other regions.ConclusionsThe fetal hippocampi possessed a prominent medial-lateral bidirectional shape growth pattern. Part of the hippocampal head adjacent to the amygdala and the hippocampal tail adjacent to the corpus callosum were restricted, which indicates that the development of the hippocampal formation was influenced by surrounding brain regions. The morphological changes of the left and right hippocampal formation are slightly different, which is not obvious. Our research can provide a morphological reference for the further study of the hippocampal formation.Part 4:A dynamic 4D template of the developing fetal hippocampal formation during second trimester. ObjectiveStudies about hippocampal formation have increasingly needed the help of hippocampal template. However, conventional templates are suitable for adult or adolescent hippocampal formation, and fetal hippocampal templates are not well developed these years. Therefore, this study intends to use 7.0T post-mortem MRI, combined with Advanced Normalization Tools (ANTs) to construct a 4D dynamic template of the developing fetal hippocampal formation during early second trimester.Materials and methods40 specimens of 14-22 GW were used for the MR 7.0T scanning and the Amira software was used to segment the hippocampal formation (see the first part). In consideration of the sample size, we divided the total 40 subject into four groups:the first group:14-16 GW; the second group:17-18 GW; the third group:19-20 GW; the fourth group:21-22 GW. Using buildtem.plateparallel.sh script of the ANTs software, each template of the hippocampal formation of corresponding group was constructed, the parameters set as the default.ResultsWe successfully constructed the 4D dynamic template of the developing fetal hippocampal formation. In the 17-18 GW, the fetal hippocampal formation has been shown to have tri-laminar appearance. At 14 to 22 GW, the fetal hippocampal formation grew rapidly, especially in the hippocampal head. The overall hippocampal formation gradually became horizontal and folded into the medial temporal lobe.ConclusionsWe firstly construct 4D dynamic template of the developing fetal hippocampal formation during the period from 14 GW to 22 GW. High field 7.0T MRI was used to make sure the template with a relatively high resolution and contrast. Our study will provide the anatomic basis for the future hippocampal studies. |
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