Our objective is to measure spatial, temporal, and directional variations in mechanical properties of the ferret brain during cortical folding. Disturbances of folding have serious and lasting consequences, but the mechanism is not understood. Van Essen (1997) hypothesized that mechanical tension in axons drives cortical folding. According to this hypothesis, tension between strongly interconnected regions of the cortex pulls these regions together, generating an outward fold (gyrus);weakly-connected regions end up separated by an inward fold (sulcus). This hypothesized mechanism encourages compact wiring (Van Essen, 1997). To evaluate such theoretical models, accurate measurements of residual stress, stiffness, and anisotropy in the developing brain are needed. Approach: Studies will be performed in the neonatal ferret. The ferret has a gyrencephalic brain which undergoes folding during the first post-natal month. Mechanical properties will be found from experimental data combined with finite element modeling. Residual stress will be estimated by measuring deformation after local cuts. Stiffness properties of the brain will be measured from shear wave speed and analysis of indentation. Diffusion tensor imaging (DTI) will provide data on tissue anisotropy, and regional distribution of motor proteins (dynein, kinesin, myosin II, myosin V) will be assessed histologically. Stiffness and residual stress are expected to vary spatially, temporally, and as a function of direction. Such variations would be critically important in brain morphogenesis.
Specific aims : In the neonatal ferret brain (1) Measure local residual stress in different locations and directions;(2) Image shear wave propagation in different directions to estimate local stiffness and anisotropy for small deformations. (3) Measure force-displacement relationships during indentation of tissue;use inverse modeling of local deformation to develop constitutive relationships for large strain. (4) Perform DTI [and histological] studies during folding to characterize anatomical, microstructural, and cellular changes. Compare spatial, directional, and developmental variations in diffusion and mechanical properties. Significance: This is the first step toward development of a rigorous biomechanical model of cortical folding, including growth. Such models are needed to understand the causal pathways of pathologies (e.g., lissencephaly, polymicrogyria) responsible for mental disability and disease (retardation, seizure).

Public Health Relevance

Disturbances of cortical folding in brain development have serious and lasting consequences, but the mechanism is not well understood. This project is the first step toward development of a rigorous biomechanical model of cortical folding, including growth. Such models are needed to understand the causal pathways of pathologies (e.g., lissencephaly, polymicrogyria) responsible for mental disability and disease (such as retardation, seizure).

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21EB005834-01A2
Application #
7472196
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Peng, Grace
Project Start
2009-06-01
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
1
Fiscal Year
2009
Total Cost
$220,022
Indirect Cost
Name
Washington University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Bayly, P V; Garbow, J R (2018) Pre-clinical MR elastography: Principles, techniques, and applications. J Magn Reson 291:73-83
Kroenke, Christopher D; Bayly, Philip V (2018) How Forces Fold the Cerebral Cortex. J Neurosci 38:767-775
Bayly, P V; Taber, L A; Kroenke, C D (2014) Mechanical forces in cerebral cortical folding: a review of measurements and models. J Mech Behav Biomed Mater 29:568-81
Knutsen, Andrew K; Kroenke, Christopher D; Chang, Yulin V et al. (2013) Spatial and temporal variations of cortical growth during gyrogenesis in the developing ferret brain. Cereb Cortex 23:488-98
Bayly, P V; Okamoto, R J; Xu, G et al. (2013) A cortical folding model incorporating stress-dependent growth explains gyral wavelengths and stress patterns in the developing brain. Phys Biol 10:016005
Chang, Yulin V (2012) Rapid B1 mapping using orthogonal, equal-amplitude radio-frequency pulses. Magn Reson Med 67:718-23
Bayly, Philip V; Clayton, Erik H; Genin, Guy M (2012) Quantitative imaging methods for the development and validation of brain biomechanics models. Annu Rev Biomed Eng 14:369-96
Okamoto, R J; Clayton, E H; Bayly, P V (2011) Viscoelastic properties of soft gels: comparison of magnetic resonance elastography and dynamic shear testing in the shear wave regime. Phys Med Biol 56:6379-400
Xu, Gang; Knutsen, Andrew K; Dikranian, Krikor et al. (2010) Axons pull on the brain, but tension does not drive cortical folding. J Biomech Eng 132:071013
Knutsen, Andrew K; Chang, Yulin V; Grimm, Cindy M et al. (2010) A new method to measure cortical growth in the developing brain. J Biomech Eng 132:101004

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