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The important mechanical parameters and their hierarchy in the growth and folding of the human brain have not been thoroughly understood. In this study, we developed a multiscale mechanical model to investigate how the interplay between initial geometrical undulations, differential tangential growth in the cortical plate, and axonal connectivity form and regulate the folding patterns of the human brain in a hierarchical order. To do so, different growth scenarios with bilayer spherical models that features initial undulations on the cortex and uniform or heterogeneous distribution of axonal fibers in the white matter were developed, statistically analyzed, and validated by the imaging observations. The results showed that the differential tangential growth is the inducer of cortical folding, and in a hierarchal order, high-amplitude initial undulations on the surface and axonal fibers in the substrate regulate the folding patterns and determine the location of gyri and sulci. The locations with dense axonal fibers after folding settle in gyri rather than sulci. The statistical results also indicated that there is a strong correlation between the location of positive (outward) and negative (inward) initial undulations and the locations of gyri and sulci after folding, respectively. In addition, the locations of 3-hinge gyral folds are strongly correlated with the initial positive undulations and locations of dense axonal fibers. As another finding, it was revealed that there is a correlation between the density of axonal fibers and local gyrification index, which has been observed in imaging studies but not yet fundamentally explained. This study is the first step in understanding the linkage between abnormal gyrification (surface morphology) and disruption in connectivity that has been observed in some brain disorders such as Autism Spectrum Disorder. Moreover, the findings of the study directly contribute to the concept of the regularity and variability of folding patterns in individual human brains.

 

The human brain development experiences a complex evolving cortical folding from a smooth surface to a convoluted ensemble of folds. Computational modeling of brain development has played an essential role in better understanding the process of cortical folding, but still leaves many questions to be answered. A major challenge faced by computational models is how to create massive brain developmental simulations with affordable computational sources to complement neuroimaging data and provide reliable predictions for brain folding. In this study, we leveraged the power of machine learning in data augmentation and prediction to develop a machine-learning-based finite element surrogate model to expedite brain computational simulations, predict brain folding morphology, and explore the underlying folding mechanism. To do so, massive finite element method (FEM) mechanical models were run to simulate brain development using the predefined brain patch growth models with adjustable surface curvature. Then, a GAN-based machine learning model was trained and validated with these produced computational data to predict brain folding morphology given a predefined initial configuration. The results indicate that the machine learning models can predict the complex morphology of folding patterns, including 3-hinge gyral folds. The close agreement between the folding patterns observed in FEM results and those predicted by machine learning models validate the feasibility of the proposed approach, offering a promising avenue to predict the brain development with given fetal brain configurations.

 

Accurate characterization of the mechanical properties of the human brain at both microscopic and macroscopic length scales is a critical requirement for modeling of traumatic brain injury and brain folding. To date, most experimental studies that employ classical tension/compression/shear tests report the mechanical properties of the brain averaged over both the gray and white matter within the macroscopic regions of interest. As a result, there is a missing correlation between the independent mechanical properties of the microscopic constituent elements and the composite bulk macroscopic mechanical properties of the tissue. This microstructural computational study aims to inversely predict the hyperelastic mechanical properties of the axonal fibers and their surrounding extracellular matrix (ECM) from the bulk tissue's mechanical properties. We develop a representative volume element (RVE) model of the bulk tissue consisting of axonal fibers and ECM with the embedded element technique. A multiobjective optimization technique is implemented to calibrate the model and establish the independent mechanical properties of axonal fibers and ECM based on seven previously reported experimental mechanical tests for bulk white matter tissue from the corpus callosum. The result of the study shows that the discrepancy between the reported values for the elastic behavior of white matter in literature stems from the anisotropy of the tissue at the microscale. The shear modulus of the axonal fiber is seven times larger than the ECM, with axonal fibers that also show greater nonlinearity, contrary to the common assumption that both components exhibit identical nonlinear characteristics. Statement of significance The reported mechanical properties of white matter microstructure used in traumatic brain injury or brain mechanics studies vary widely, in some cases by up to two orders of magnitude. Currently, the material parameters of the white matter microstructure are identified by a single loading mode or ultimately two modes of the bulk tissue. The presented material models only define the response of the bulk and homogenized white matter at a macroscopic scale and cannot explicitly capture the connection between the material properties of microstructure and bulk structure. To fill this knowledge gap, our study characterizes the hyperelastic material properties of axonal fibers and ECM using microscale computational modeling and multiobjective optimization. The hyperelastic material properties for axonal fibers and ECM presented in this study are more accurate than previously proposed because they have been optimized using seven or six loading modes of the bulk tissue, which were previously limited to only two of the seven possible loading modes. As such, the predicted values with high accuracy could be used in various computational modeling studies. The systematic characterization of the material properties of the human brain tissue at both macro- and microscales will lead to more accurate computational predictions, which will enable a better understanding of injury criteria, and has a positive impact on the improved development of smart protection systems, and more accurate prediction of brain development and disease progression. 

Abstract The 3-hinge gyral folding is the conjunction of gyrus crest lines from three different orientations. Previous studies have not explored the possible mechanisms of formation of such 3-hinge gyri, which are preserved across species in primate brains. We develop a biomechanical model to mimic the formation of 3-hinge patterns on a real brain and determine how special types of 3-hinge patterns form in certain areas of the model. Our computational and experimental imaging results show that most tertiary convolutions and exact locations of 3-hinge patterns after growth and folding are unpredictable, but they help explain the consistency of locations and patterns of certain 3-hinge patterns. Growing fibers within the white matter is posited as a determining factor to affect the location and shape of these 3-hinge patterns. Even if the growing fibers do not exert strong enough forces to guide gyrification directly, they still may seed a heterogeneous growth profile that leads to the formation of 3-hinge patterns in specific locations. A minor difference in initial morphology between two growing model brains can lead to distinct numbers and locations of 3-hinge patterns after folding. 

Tissue interfaced electronics have become promising candidates for transcending beyond conventional diagnostic technology, enabling chronic, quantitative health monitoring possibilities; however, these systems have primarily relied on impenetrable materials that contribute to the mechanical and physical mismatch of bioelectronic interfaces. Inspired by the soft mechanics and physical architecture of the epidermal extracellular matrix, this study presents a 3D microporous, fibrous mesh of polydimethylsiloxane for epidermal electronics. The resulting elastic microfiber mat, exhibits a minimal mechanical footprint with analogous viscoelastic behavior, cytocompatibility, and biofluid‐permeable interface capable of small molecule, gas, and transdermal water diffusion. Electrocardiography electrodes heterogeneously integrate within the synthetic electronic‐extracellular matrix (e‐ECM) membrane and achieve chronic high resolution biopotential monitoring during typically debilitating environments (e.g., vigorous sweating) for conventional bioelectronics. The e‐ECM platform provides a substrate template for open‐mesh electronics, enabling advanced implementations in long‐term quantitative analysis monitoring for wearable and implantable devices.