Longitudinal MRI of the developing ferret brain reveals regional variations in timing and rate of growth.

Normative ferret brain development was characterized using magnetic resonance imaging. Brain growth was longitudinally monitored in 10 ferrets (equal numbers of males and females) from postnatal day 8 (P8) through P38 in 6-d increments. Template T2-weighted images were constructed at each age, and these were manually segmented into 12 to 14 brain regions. A logistic growth model was used to fit data from whole brain volumes and 8 of the individual regions in both males and females. More protracted growth was found in males, which results in larger brains; however, sex differences were not apparent when results were corrected for body weight. Additionally, surface models of the developing cortical plate were registered to one another using the anatomically-constrained Multimodal Surface Matching algorithm. This, in turn, enabled local logistic growth parameters to be mapped across the cortical surface. A close similarity was observed between surface area expansion timing and previous reports of the transverse neurogenic gradient in ferrets. Regional variation in the extent of surface area expansion and the maximum expansion rate was also revealed. This characterization of normative brain growth over the period of cerebral cortex folding may serve as a reference for ferret studies of brain development.

Molecular and mechanical signals determine morphogenesis of the cerebral hemispheres in the chicken embryo.

During embryonic development, the telecephalon undergoes extensive growth and cleaves into right and left cerebral hemispheres. Although molecular signals have been implicated in this process and linked to congenital abnormalities, few studies have examined the role of mechanical forces. In this study, we quantified morphology, cell proliferation and tissue growth in the forebrain of chicken embryos during Hamburger-Hamilton stages 17-21. By altering embryonic cerebrospinal fluid pressure during development, we found that neuroepithelial growth depends on not only chemical morphogen gradients but also mechanical feedback. Using these data, as well as published information on morphogen activity, we developed a chemomechanical growth law to mathematically describe growth of the neuroepithelium. Finally, we constructed a three-dimensional computational model based on these laws, with all parameters based on experimental data. The resulting model predicts forebrain shapes consistent with observations in normal embryos, as well as observations under chemical or mechanical perturbation. These results suggest that molecular and mechanical signals play important roles in early forebrain morphogenesis and may contribute to the development of congenital malformations.

Dynamic patterns of cortical expansion during folding of the preterm human brain.

During the third trimester of human brain development, the cerebral cortex undergoes dramatic surface expansion and folding. Physical models suggest that relatively rapid growth of the cortical gray matter helps drive this folding, and structural data suggest that growth may vary in both space (by region on the cortical surface) and time. In this study, we propose a unique method to estimate local growth from sequential cortical reconstructions. Using anatomically constrained multimodal surface matching (aMSM), we obtain accurate, physically guided point correspondence between younger and older cortical reconstructions of the same individual. From each pair of surfaces, we calculate continuous, smooth maps of cortical expansion with unprecedented precision. By considering 30 preterm infants scanned two to four times during the period of rapid cortical expansion (28-38 wk postmenstrual age), we observe significant regional differences in growth across the cortical surface that are consistent with the emergence of new folds. Furthermore, these growth patterns shift over the course of development, with noninjured subjects following a highly consistent trajectory. This information provides a detailed picture of dynamic changes in cortical growth, connecting what is known about patterns of development at the microscopic (cellular) and macroscopic (folding) scales. Since our method provides specific growth maps for individual brains, we are also able to detect alterations due to injury. This fully automated surface analysis, based on tools freely available to the brain-mapping community, may also serve as a useful approach for future studies of abnormal growth due to genetic disorders, injury, or other environmental variables.

A new hypothesis for foregut and heart tube formation based on differential growth and actomyosin contraction.

For decades, it was commonly thought that the bilateral heart fields in the early embryo fold directly towards the midline, where they meet and fuse to create the primitive heart tube. Recent studies have challenged this view, however, suggesting that the heart fields fold diagonally. As early foregut and heart tube morphogenesis are intimately related, this finding also raises questions concerning the traditional view of foregut formation. Here, we combine experiments on chick embryos with computational modeling to explore a new hypothesis for the physical mechanisms of heart tube and foregut formation. According to our hypothesis, differential anisotropic growth between mesoderm and endoderm drives diagonal folding. Then, active contraction along the anterior intestinal portal generates tension to elongate the foregut and heart tube. We test this hypothesis using biochemical perturbations of cell proliferation and contractility, as well as computational modeling based on nonlinear elasticity theory including growth and contraction. The present results generally support the view that differential growth and actomyosin contraction drive formation of the foregut and heart tube in the early chick embryo.

Effects of stress-dependent growth on evolution of sulcal direction and curvature in models of cortical folding.

The majority of human brain folding occurs during the third trimester of gestation. Although many studies have investigated the physical mechanisms of brain folding, a comprehensive understanding of this complex process has not yet been achieved. In mechanical terms, the "differential growth hypothesis" suggests that the formation of folds results from a difference in expansion rates between cortical and subcortical layers, which eventually leads to mechanical instability akin to buckling. It has also been observed that axons, a substantial component of subcortical tissue, can elongate or shrink under tensile or compressive stress, respectively. Previous work has proposed that this cell-scale behavior in aggregate can produce stress-dependent growth in the subcortical layers. The current study investigates the potential role of stress-dependent growth on cortical surface morphology, in particular the variations in folding direction and curvature over the course of development. Evolution of sulcal direction and mid-cortical surface curvature were calculated from finite element simulations of three-dimensional folding in four different initial geometries: (i) sphere; (ii) axisymmetric oblate spheroid; (iii) axisymmetric prolate spheroid; and (iv) triaxial spheroid. The results were compared to mid-cortical surface reconstructions from four preterm human infants, imaged and analyzed at four time points during the period of brain folding. Results indicate that models incorporating subcortical stress-dependent growth predict folding patterns that more closely resemble those in the developing human brain. Statement of Significance: Cortical folding is a critical process in human brain development. Aberrant folding is associated with disorders such as autism and schizophrenia, yet our understanding of the physical mechanism of folding remains limited. Ultimately mechanical forces must shape the brain. An important question is whether mechanical forces simply deform tissue elastically, or whether stresses in the tissue modulate growth. Evidence from this paper, consisting of quantitative comparisons between patterns of folding in the developing human brain and corresponding patterns in simulations, supports a key role for stress-dependent growth in cortical folding.

Multi-scale measurement of stiffness in the developing ferret brain.

Cortical folding is an important process during brain development, and aberrant folding is linked to disorders such as autism and schizophrenia. Changes in cell numbers, size, and morphology have been proposed to exert forces that control the folding process, but these changes may also influence the mechanical properties of developing brain tissue. Currently, the changes in tissue stiffness during brain folding are unknown. Here, we report stiffness in the developing ferret brain across multiple length scales, emphasizing changes in folding cortical tissue. Using rheometry to measure the bulk properties of brain tissue, we found that overall brain stiffness increases with age over the period of cortical folding. Using atomic force microscopy to target the cortical plate, we found that the occipital cortex increases in stiffness as well as stiffness heterogeneity over the course of development and folding. These findings can help to elucidate the mechanics of the cortical folding process by clarifying the concurrent evolution of tissue properties.

Increased Prevalence of Sensory Processing Issues in Pediatric Gastrointestinal Patient Population.

Background Sensory processing dysfunction in children has been linked to attention-deficit/hyperactivity disorder, autism, feeding disorders, and functional abdominal pain. However, little is known about sensory processing in the broader pediatric gastroenterology population. Objective To characterize frequency and type of sensory processing dysfunction seen in pediatric gastroenterology compared to a general pediatric population. Methods The Short Sensory Profile 2 was administered to the parents of children ranging 3-14 years, being seen in a pediatric gastrointestinal (GI) subspecialty clinic or general pediatric clinic. Short Sensory Profile 2 scores from age- and gender-matched groups were compared with nonparametric statistics. Results Sensory processing dysfunction was increased in children seen in the GI clinic compared to children in the general pediatric clinic. Short Sensory Profile 2 quadrant analysis revealed greatest differences in avoiding, primarily in young females of the GI population. Conclusion Children presenting to a pediatric GI clinic demonstrate greater sensory processing dysfunction compared to children in a general pediatric practice.

A model of tension-induced fiber growth predicts white matter organization during brain folding.

The past decade has experienced renewed interest in the physical processes that fold the developing cerebral cortex. Biomechanical models and experiments suggest that growth of the cortex, outpacing growth of underlying subcortical tissue (prospective white matter), is sufficient to induce folding. However, current models do not explain the well-established links between white matter organization and fold morphology, nor do they consider subcortical remodeling that occurs during the period of folding. Here we propose a framework by which cortical folding may induce subcortical fiber growth and organization. Simulations incorporating stress-induced fiber elongation indicate that subcortical stresses resulting from folding are sufficient to induce stereotyped fiber organization beneath gyri and sulci. Model predictions are supported by high-resolution ex vivo diffusion tensor imaging of the developing rhesus macaque brain. Together, results provide support for the theory of cortical growth-induced folding and indicate that mechanical feedback plays a significant role in brain connectivity.

Contraction and stress-dependent growth shape the forebrain of the early chicken embryo.

During early vertebrate development, local constrictions, or sulci, form to divide the forebrain into the diencephalon, telencephalon, and optic vesicles. These partitions are maintained and exaggerated as the brain tube inflates, grows, and bends. Combining quantitative experiments on chick embryos with computational modeling, we investigated the biophysical mechanisms that drive these changes in brain shape. Chemical perturbations of contractility indicated that actomyosin contraction plays a major role in the creation of initial constrictions (Hamburger-Hamilton stages HH11-12), and fluorescent staining revealed that F-actin is circumferentially aligned at all constrictions. A finite element model based on these findings shows that the observed shape changes are consistent with circumferential contraction in these regions. To explain why sulci continue to deepen as the forebrain expands (HH12-20), we speculate that growth depends on wall stress. This idea was examined by including stress-dependent growth in a model with cerebrospinal fluid pressure and bending (cephalic flexure). The results given by the model agree with observed morphological changes that occur in the brain tube under normal and reduced eCSF pressure, quantitative measurements of relative sulcal depth versus time, and previously published patterns of cell proliferation. Taken together, our results support a biphasic mechanism for forebrain morphogenesis consisting of differential contractility (early) and stress-dependent growth (late).