Scaling patterns of cortical folding and thickness in early human brain development in comparison with primates.

Across mammalia, brain morphology follows specific scaling patterns. Bigger bodies have bigger brains, with surface area outpacing volume growth, resulting in increased foldedness. We have recently studied scaling rules of cortical thickness, both local and global, finding that the cortical thickness difference between thick gyri and thin sulci also increases with brain size and foldedness. Here, we investigate early brain development in humans, using subjects from the Developing Human Connectome Project, scanned shortly after pre-term or full-term birth, yielding magnetic resonance images of the brain from 29 to 43 postmenstrual weeks. While the global cortical thickness does not change significantly during this development period, its distribution does, with sulci thinning, while gyri thickening. By comparing our results with our recent work on humans and 11 non-human primate species, we also compare the trajectories of primate evolution with human development, noticing that the 2 trends are distinct for volume, surface area, cortical thickness, and gyrification index. Finally, we introduce the global shape index as a proxy for gyrification index; while correlating very strongly with gyrification index, it offers the advantage of being calculated only from local quantities without generating a convex hull or alpha surface.

Axonal tension contributes to consistent fold placement.

Cortical folding is a critical process during brain development, resulting in morphologies that are both consistent and distinct between individuals and species. While earlier studies have highlighted important aspects of cortical folding, most existing computational models, based on the differential growth theory, fall short of explaining why folds tend to appear in particular locations. The axon tension hypothesis may provide insight into this conundrum; however, there has been significant controversy about a potential role of axonal tension during the gyrification. The common opinion in the field is that axonal tension is inadequate to drive gyrification, but we currently run the risk of discarding this hypothesis without comprehensively studying the role of axonal tension. Here we propose a novel bi-layered finite element model incorporating the two theories, including characteristic axonal tension in the subcortex and differential cortical growth. We show that axon tension can serve as a perturbation sufficient to trigger buckling in simulations; similarly to other types of perturbations, the natural stability behavior of the system tends to determine some characteristics of the folding morphology (e.g. the wavelength) while the perturbation determines the location of folds. Certain geometries, however, can interact or compete with the natural stability of the system to change the wavelength. When multiple perturbations are present, they similarly compete with each other. We found that an axon bundle of reasonable size will overpower up to a 5% thickness perturbation (typical in the literature) and determine fold placement. Finally, when multiple axon tracts are present, even a slight difference in axon stiffness, representing the heterogeneity of axonal connections, is enough to significantly change the folding pattern. While the simulations presented here are a very simple representation of white matter connectivity, our findings point to urgent future research on the role of axon connectivity in cortical folding.

Systematic cortical thickness and curvature patterns in primates.

Humans are known to have significant and consistent differences in thickness throughout the cortex, with thick outer gyral folds and thin inner sulcal folds. Our previous work has suggested a mechanical basis for this thickness pattern, with the forces generated during cortical folding leading to thick gyri and thin sulci, and shown that cortical thickness varies along a gyral-sulcal spectrum in humans. While other primate species are expected to exhibit similar patterns of cortical thickness, it is currently unknown how these patterns scale across different sizes, forms, and foldedness. Among primates, brains vary enormously from roughly the size of a grape to the size of a grapefruit, and from nearly smooth to dramatically folded; of these, human brains are the largest and most folded. These variations in size and form make comparative neuroanatomy a rich resource for investigating common trends that transcend differences between species. In this study, we examine 12 primate species in order to cover a wide range of sizes and forms, and investigate the scaling of their cortical thickness relative to the surface geometry. The 12 species were selected due to the public availability of either reconstructed surfaces and/or population templates. After obtaining or reconstructing 3D surfaces from publicly available neuroimaging data, we used our surface-based computational pipeline (https://github.com/mholla/curveball) to analyze patterns of cortical thickness and folding with respect to size (total surface area), geometry (i.e. curvature, shape, and sulcal depth), and foldedness (gyrification). In all 12 species, we found consistent cortical thickness variations along a gyral-sulcal spectrum, with convex shapes thicker than concave shapes and saddle shapes in between. Furthermore, we saw an increasing thickness difference between gyri and sulci as brain size increases. Our results suggest a systematic folding mechanism relating local cortical thickness to geometry. Finally, all of our reconstructed surfaces and morphometry data are available for future research in comparative neuroanatomy.

Orchestrated neuronal migration and cortical folding: A computational and experimental study.

Brain development involves precisely orchestrated genetic, biochemical, and mechanical events. At the cellular level, neuronal proliferation in the innermost zone of the brain followed by migration towards the outermost layer results in a rapid increase in brain surface area, outpacing the volumetric growth of the brain, and forming the highly folded cortex. This work aims to provide mechanistic insights into the process of brain development and cortical folding using a biomechanical model that couples cell division and migration with volumetric growth. Unlike phenomenological growth models, our model tracks the spatio-temporal development of cohorts of neurons born at different times, with each cohort modeled separately as an advection-diffusion process and the total cell density determining the extent of volume growth. We numerically implement our model in Abaqus/Standard (2020) by writing user-defined element (UEL) subroutines. For model calibration, we apply in utero electroporation (IUE) to ferret brains to visualize and track cohorts of neurons born at different stages of embryonic development. Our calibrated simulations of cortical folding align qualitatively with the ferret experiments. We have made our experimental data and finite-element implementation available online to offer other researchers a modeling platform for future study of neurological disorders associated with atypical neurodevelopment and cortical malformations.

Cortical thickness systematically varies with curvature and depth in healthy human brains.

Cortical thickness varies throughout the cortex in a systematic way. However, it is challenging to investigate the patterns of cortical thickness due to the intricate geometry of the cortex. The cortex has a folded nature both in radial and tangential directions which forms not only gyri and sulci but also tangential folds and intersections. In this article, cortical curvature and depth are used to characterize the spatial distribution of the cortical thickness with much higher resolution than conventional regional atlases. To do this, a computational pipeline was developed that is capable of calculating a variety of quantitative measures such as surface area, cortical thickness, curvature (mean curvature, Gaussian curvature, shape index, intrinsic curvature index, and folding index), and sulcal depth. By analyzing 501 neurotypical adult human subjects from the ABIDE-I dataset, we show that cortex has a very organized structure and cortical thickness is strongly correlated with local shape. Our results indicate that cortical thickness consistently increases along the gyral-sulcal spectrum from concave to convex shape, encompassing the saddle shape along the way. Additionally, tangential folds influence cortical thickness in a similar way as gyral and sulcal folds; outer folds are consistently thicker than inner.

The Geometry of Incompatibility in Growing Soft Tissues: Theory and Numerical Characterization.

Tissues in vivo are not stress-free. As we grow, our tissues adapt to different physiological and disease conditions through growth and remodeling. This adaptation occurs at the microscopic scale, where cells control the microstructure of their immediate extracellular environment to achieve homeostasis. The local and heterogeneous nature of this process is the source of residual stresses. At the macroscopic scale, growth and remodeling can be accurately captured with the finite volume growth framework within continuum mechanics, which is akin to plasticity. The multiplicative split of the deformation gradient into growth and elastic contributions brings about the notion of incompatibility as a plausible description for the origin of residual stress. Here we define the geometric features that characterize incompatibility in biological materials. We introduce the geometric incompatibility tensor for different growth types, showing that the constraints associated with growth lead to specific patterns of the incompatibility metrics. To numerically investigate the distribution of incompatibility measures, we implement the analysis within a finite element framework. Simple, illustrative examples are shown first to explain the main concepts. Then, numerical characterization of incompatibility and residual stress is performed on three biomedical applications: brain atrophy, skin expansion, and cortical folding. Our analysis provides new insights into the role of growth in the development of tissue defects and residual stresses. Thus, we anticipate that our work will further motivate additional research to characterize residual stresses in living tissue and their role in development, disease, and clinical intervention.

Symmetry Breaking in Wrinkling Patterns: Gyri Are Universally Thicker than Sulci.

Wrinkling instabilities appear in soft materials when a flat elastic layer on an elastic substrate is sufficiently stressed that it buckles with a wavy pattern to minimize the energy of the system. This instability is known to play an important role in engineering, but it also appears in many biological systems. In these systems, the stresses responsible for the wrinkling instability are often created through differential growth of the two layers. Beyond the instability, the upper and lower sides of the elastic layer are subject to different forces. This difference in forces leads to an interesting symmetry breaking whereby the thickness becomes larger at ridges than at valleys. Here we carry out an extensive analysis of this phenomenon by combining analytical, computational, and simple polymer experiments to show that symmetry breaking is a generic property of such systems. We apply our idea to the cortical folding of the brain for which it has been known for over a century that there is a thickness difference between gyri and sulci. An extensive analysis of hundreds of human brains reveals a systematic region-dependent thickness variation. Our results suggest that the evolving thickness patterns during brain development, similar to our polymer experiments, follow simple physics-based laws: Gyri are universally thicker than sulci.

Investigation of direction- and age-dependent prestretch in mouse cranial dura mater.

Cranial dura mater is a dense interwoven vascularized connective tissue that helps regulate neurocranial remodeling by responding to strains from the growing brain. Previous ex vivo experimentation has failed to account for the role of prestretch in the mechanical behavior of the dura. Here we aim to estimate the prestretch in mouse cranial dura mater and determine its dependency on direction and age. We performed transverse and longitudinal incisions in parietal dura excised from newborn (day ∼ 4) and mature (12 weeks) mice and calculated the ex vivo normalized incision opening (measured width over length). Then, similar incisions were simulated under isotropic stretching within Abaqus/Standard. Finally, prestretch was estimated by comparing the ex vivo and in silico normalized openings. There were no significant differences between the neonatal and adult mice when comparing cuts in the same direction, but adult mice were found to have significantly greater stretch in the anterior-posterior direction than in the medial-lateral direction, while neonatal dura was essentially isotropic. Additionally, our simulations show that increasing curvature impacts the incision opening, indicating that flat in silico models may overestimate prestretch.

On the mechanics of thin films and growing surfaces.

Many living structures are coated by thin films, which have distinct mechanical properties from the bulk. In particular, these thin layers may grow faster or slower than the inner core. Differential growth creates a balanced interplay between tension and compression and plays a critical role in enhancing structural rigidity. Typical examples with a compressive outer surface and a tensile inner core are the petioles of celery, caladium, or rhubarb. While plant physiologists have studied the impact of tissue tension on plant rigidity for more than a century, the fundamental theory of growing surfaces remains poorly understood. Here, we establish a theoretical and computational framework for continua with growing surfaces and demonstrate its application to classical phenomena in plant growth. To allow the surface to grow independently of the bulk, we equip it with its own potential energy and its own surface stress. We derive the governing equations for growing surfaces of zero thickness and obtain their spatial discretization using the finite-element method. To illustrate the features of our new surface growth model we simulate the effects of growth-induced longitudinal tissue tension in a stalk of rhubarb. Our results demonstrate that different growth rates create a mechanical environment of axial tissue tension and residual stress, which can be released by peeling off the outer layer. Our novel framework for continua with growing surfaces has immediate biomedical applications beyond these classical model problems in botany: it can be easily extended to model and predict surface growth in asthma, gastritis, obstructive sleep apnoea, brain development, and tumor invasion. Beyond biology and medicine, surface growth models are valuable tools for material scientists when designing functionalized surfaces with distinct user-defined properties.

Computational models of cortical folding: A review of common approaches.

The process of gyrification, by which the brain develops the intricate pattern of gyral hills and sulcal valleys, is the result of interactions between biological and mechanical processes during brain development. Researchers have developed a vast array of computational models in order to investigate cortical folding. This review aims to summarize these studies, focusing on five essential elements of the brain that affect development and gyrification and how they are represented in computational models: (i) the constraints of skull, meninges, and cerebrospinal fluid; (ii) heterogeneity of cortical layers and regions; (iii) anisotropic behavior of subcortical fiber tracts; (iv) material properties of brain tissue; and (v) the complex geometry of the brain. Finally, we highlight areas of need for future simulations of brain development.

Numerical investigation of biomechanically coupled growth in cortical folding.

Cortical folding-the process of forming the characteristic gyri (hills) and sulci (valleys) of the cortex-is a highly dynamic process that results from the interaction between gene expression, cellular mechanisms, and mechanical forces. Like many other cells, neurons are sensitive to their mechanical environment. Because of this, cortical growth may not happen uniformly throughout gyri and sulci after the onset of cortical folding, which is accompanied by patterns of tension and compression in the surrounding tissue. Here, as an extension of our previous work, we introduce a biomechanically coupled growth model to investigate the importance of interaction between biological growth and mechanical cues during brain development. Our earlier simulations of cortical growth consisted of a homogeneous growing cortex attached to an elastic subcortex. Here, we let the evolution of cortical growth depend on a geometrical quantity-the mean curvature of the cortex-to achieve preferential growth in either gyri or sulci. As opposed to the popular pre-patterning hypothesis, our model treats inhomogeneous cortical growth as the result of folding rather than the cause. The model is implemented numerically in a commercial finite element software Abaqus/Explicit in Abaqus reference manuals, Dassault Systemes Simulia, Providence (2019) by writing user-defined material subroutine (VUMAT). Our simulations show that gyral-sulcal thickness variations are a phenomenon particular to low stiffness ratios. In comparison with cortical thickness measurements of [Formula: see text] human brains via a consistent sampling scheme, our simulations with similar cortical and subcortical stiffnesses suggest that cortical growth is higher in gyri than in sulci.

Folding drives cortical thickness variations.

The cortical thickness is a characteristic biomarker for a wide variety of neurological disorders. While the structural organization of the cerebral cortex is tightly regulated and evolutionarily preserved, its thickness varies widely between 1.5 and 4.5 mm across the healthy adult human brain. It remains unclear whether these thickness variations are a cause or consequence of cortical development. Recent studies suggest that cortical thickness variations are primarily a result of genetic effects. Previous studies showed that a simple homogeneous bilayered system with a growing layer on an elastic substrate undergoes a unique symmetry breaking into a spatially heterogeneous system with discrete gyri and sulci. Here, we expand on that work to explore the evolution of cortical thickness variations over time to support our finding that cortical pattern formation and thickness variations can be explained - at least in part - by the physical forces that emerge during cortical folding. Strikingly, as growth progresses, the developing gyri universally thicken and the sulci thin, even in the complete absence of regional information. Using magnetic resonance images, we demonstrate that these naturally emerging thickness variations agree with the cortical folding pattern in n = 9 healthy adult human brains, in n = 564 healthy human brains ages 7-64, and in n = 73 infant brains scanned at birth, and at ages one and two. Additionally, we show that cortical organoids develop similar patterns throughout their growth. Our results suggest that genetic, geometric, and physical events during brain development are closely interrelated. Understanding regional and temporal variations in cortical thickness can provide insight into the evolution and causative factors of neurological disorders, inform the diagnosis of neurological conditions, and assess the efficacy of treatment options.

Growth and remodeling play opposing roles during postnatal human heart valve development.

Tissue growth and remodeling are known to govern mechanical homeostasis in biological tissue, but their relative contributions to homeostasis remain unclear. Here, we use mechanical models, fueled by experimental findings, to demonstrate that growth and remodeling have different effects on heart valve stretch homeostasis during physiological postnatal development. Two developmental stages were considered: early-stage (from infant to adolescent) and late-stage (from adolescent to adult) development. Our models indicated that growth and remodeling play opposing roles in preserving tissue stretch and with time. During early-stage development, excessive tissue stretch was decreased by tissue growth and increased by remodeling. In contrast, during late-stage development tissue stretch was decreased by remodeling and increased by growth. Our findings contribute to an improved understanding of native heart valve adaptation throughout life, and are highly relevant for the development of tissue-engineered heart valves.

Emerging Brain Morphologies from Axonal Elongation.

Understanding the characteristic morphology of our brain remains a challenging, yet important task in human evolution, developmental biology, and neurosciences. Mathematical modeling shapes our understanding of cortical folding and provides functional relations between cortical wavelength, thickness, and stiffness. Yet, current mathematical models are phenomenologically isotropic and typically predict non-physiological, periodic folding patterns. Here we establish a mechanistic model for cortical folding, in which macroscopic changes in white matter volume are a natural consequence of microscopic axonal growth. To calibrate our model, we consult axon elongation experiments in chick sensory neurons. We demonstrate that a single parameter, the axonal growth rate, explains a wide variety of in vitro conditions including immediate axonal thinning and gradual thickness restoration. We embed our axonal growth model into a continuum model for brain development using axonal orientation distributions motivated by diffusion spectrum imaging. Our simulations suggest that white matter anisotropy-as an emergent property from directional axonal growth-intrinsically induces symmetry breaking, and predicts more physiological, less regular morphologies with regionally varying gyral wavelengths and sulcal depths. Mechanistic modeling of brain development could establish valuable relationships between brain connectivity, brain anatomy, and brain function.

Growth on demand: reviewing the mechanobiology of stretched skin.

Skin is a highly dynamic, autoregulated, living system that responds to mechanical stretch through a net gain in skin surface area. Tissue expansion uses the concept of controlled overstretch to grow extra skin for defect repair in situ. While the short-term mechanics of stretched skin have been studied intensely by testing explanted tissue samples ex vivo, we know very little about the long-term biomechanics and mechanobiology of living skin in vivo. Here we explore the long-term effects of mechanical stretch on the characteristics of living skin using a mathematical model for skin growth. We review the molecular mechanisms by which skin responds to mechanical loading and model their effects collectively in a single scalar-valued internal variable, the surface area growth. This allows us to adopt a continuum model for growing skin based on the multiplicative decomposition of the deformation gradient into a reversible elastic and an irreversible growth part. To demonstrate the inherent modularity of this approach, we implement growth as a user-defined constitutive subroutine into the general purpose implicit finite element program Abaqus/Standard. To illustrate the features of the model, we simulate the controlled area growth of skin in response to tissue expansion with multiple filling points in time. Our results demonstrate that the field theories of continuum mechanics can reliably predict the manipulation of thin biological membranes through mechanical overstretch. Our model could serve as a valuable tool to rationalize clinical process parameters such as expander geometry, expander size, filling volume, filling pressure, and inflation timing to minimize tissue necrosis and maximize patient comfort in plastic and reconstructive surgery. While initially developed for growing skin, our model can easily be generalized to arbitrary biological structures to explore the physiology and pathology of stretch-induced growth of other living systems such as hearts, arteries, bladders, intestines, ureters, muscles, and nerves.

Projeto Comunidade em Movimento: a experiência multiprofissional na Atenção Primária à Saúde / Project Comunity in Motion: The multidisciplinary experience in Primary Health Care

O Projeto Comunidade em Movimento, vinculado ao Programa Pró-PetSaúde do Ministério da Saúde é um modelo de intervenção multiprofissional de base comunitária desenvolvido na Estratégia Saúde da Família de Cuiabá. Voltado à promoção da saúde e prevenção das doenças crônicas não transmissíveis em consonância com as diretrizes das políticas governamentais que enfatizam as práticas corporais e a alimentação saudável, o projeto oferece exercícios físicos supervisionados (2x/semana), educação em saúde, estruturação e estímulo dos conselhos gestores e outras atividades desenvolvidas por alunos, profissionais do serviço e docentes dos cursos de Educação Física, Enfermagem, Medicina, Nutrição, Saúde Coletiva e Serviço Social. Esperamos que intervenções como esta sirvam de modelo para os profissionais, gestores da saúde e universidades.

The "Community in Motion" Project, linked to the Pro-PetSaúde Program of the Ministry of Health, is a multiprofessional intervention model developed by the Health Family Strategy in community-based settings of Cuiabá. Aimed to the health promotion and prevention of chronic diseases, the project is aligned with government policies that emphasize the body practices and healthy eating, by offering supervised exercises (2x/week), health education activities, encouragement for the implementation of management councils and other activities developed by students, health professionals and faculty professors from Physical Education, Nursing, Medicine, Nutrition, Public Health and Social Service. We hope that interventions such as this can serve as a model for professionals, health managers and universities.