title: Folding, But Not Surface Area Expansion, Is Associated with Cellular Morphological Maturation in the Fetal Cerebral Cortex.
abstract: Altered macroscopic anatomical characteristics of the cerebral cortex have been identified in individuals affected by various neurodevelopmental disorders. However, the cellular developmental mechanisms that give rise to these abnormalities are not understood. Previously, advances in image reconstruction of diffusion magnetic resonance imaging (MRI) have made possible high-resolutionin uteromeasurements of water diffusion anisotropy in the fetal brain. Here, diffusion anisotropy within the developing fetal cerebral cortex is longitudinally characterized in the rhesus macaque, focusing on gestation day (G85) through G135 of the 165 d term. Additionally, for subsets of animals characterized at G90 and G135, immunohistochemical staining was performed, and 3D structure tensor analyses were used to identify the cellular processes that most closely parallel changes in water diffusion anisotropy with cerebral cortical maturation. Strong correlations were found between maturation of dendritic arbors on the cellular level and the loss of diffusion anisotropy with cortical development. In turn, diffusion anisotropy changes were strongly associated both regionally and temporally with cortical folding. Notably, the regional and temporal dependence of diffusion anisotropy and folding were distinct from the patterns observed for cerebral cortical surface area expansion. These findings strengthen the link proposed in previous studies between cellular-level changes in dendrite morphology and noninvasive diffusion MRI measurements of the developing cerebral cortex and support the possibility that, in gyroencephalic species, structural differentiation within the cortex is coupled to the formation of gyri and sulci.SIGNIFICANCE STATEMENTAbnormal brain morphology has been found in populations with neurodevelopmental disorders. However, the mechanisms linking cellular level and macroscopic maturation are poorly understood, even in normal brains. This study contributes new understanding to this subject using serialin uteroMRI measurements of rhesus macaque fetuses, from which macroscopic and cellular information can be derived. We found that morphological differentiation of dendrites was strongly associated both regionally and temporally with folding of the cerebral cortex. Interestingly, parallel associations were not observed with cortical surface area expansion. These findings support the possibility that perturbed morphological differentiation of cells within the cortex may underlie abnormal macroscopic characteristics of individuals affected by neurodevelopmental disorders.
authors.affiliation: Divisions of Neuroscience.
authors.forename: Xiaojie
authors.identifier: 0000-0001-5557-6048
authors.initials: X
authors.lastname: Wang
authors.affiliation: Biomedical Image Computing Group, Departments of Pediatrics, Bioengineering and Radiology, University of Washington, Seattle, Washington 98105, and.
authors.forename: Colin
authors.initials: C
authors.lastname: Studholme
authors.affiliation: Reproductive Sciences, and.
authors.forename: Peta L
authors.identifier: 0000-0002-0750-0388
authors.initials: PL
authors.lastname: Grigsby
authors.affiliation: Cardiometabolic Health, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006.
authors.forename: Antonio E
authors.initials: AE
authors.lastname: Frias
authors.affiliation: Divisions of Neuroscience.
authors.forename: Verginia C
authors.identifier: 0000-0002-8858-3241
authors.initials: VC
authors.lastname: Cuzon Carlson
authors.affiliation: Divisions of Neuroscience, kroenkec@ohsu.edu.|Advanced Imaging Research Center, Oregon Health & Science University, Portland, Oregon 97214.
authors.forename: Christopher D
authors.identifier: 0000-0001-7398-3632
authors.initials: CD
authors.lastname: Kroenke
mesh_terms: D000367:Age Factors; D000818:Animals; D016880:Anisotropy; D001931:Brain Mapping; D002540:Cerebral Cortex / Q000166:cytology* / Q000000981:diagnostic imaging / Q000196:embryology*; D056324:Diffusion Tensor Imaging; D004622:Embryo, Mammalian / Q000166:cytology* / Q000000981:diagnostic imaging; D047108:Embryonic Development / Q000502:physiology; D005260:Female; D005865:Gestational Age; D007091:Image Processing, Computer-Assisted; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009434:Neural Pathways / Q000196:embryology / Q000502:physiology; D038081:Organogenesis; D011247:Pregnancy; D013223:Statistics as Topic; D014746:Vimentin / Q000378:metabolism
chemical_list: D008869:Microtubule-Associated Proteins; D014746:Vimentin
keywords: brain development; diffusion; fetal brain; gyrification; in utero; magnetic resonance imaging