MECHANICAL CHANGES IN THE DEVELOPING BRAIN

描述（由申请人提供）：我们的目标是测量雪貂大脑皮层折叠过程中机械特性的空间、时间和方向变化。折叠的干扰具有严重和持久的后果，但其机制尚不清楚。Van Essen（1997）假设轴突的机械张力驱动皮层折叠。根据这一假说，大脑皮层紧密相连区域之间的张力将这些区域拉在一起，产生向外折叠（脑回）；弱连接的区域最终被向内的褶皱（沟）分开。这种假设的机制鼓励紧凑的布线（Van Essen, 1997）。为了评估这些理论模型，需要对发育中的大脑的残余应力、刚度和各向异性进行精确测量。方法：研究将在新生雪貂中进行。雪貂有一个脑回，在出生后的第一个月发生折叠。力学性能将从实验数据结合有限元建模得到。残余应力将通过测量局部切割后的变形来估计。脑的刚度特性将通过横波速度和压痕分析来测量。弥散张量成像（DTI）将提供组织各向异性的数据，并对运动蛋白（动力蛋白、运动蛋白、肌球蛋白II、肌球蛋白V）的区域分布进行组织学评估。预计刚度和残余应力在空间上、时间上和方向上都是变化的。这种变异对大脑的形态发生至关重要。具体目的：在新生雪貂大脑中(1)测量不同位置和方向的局部残余应力；(2)图像横波在不同方向上传播，以估计局部刚度和小变形的各向异性。(3)测量组织压痕过程中的力-位移关系；使用局部变形的逆建模来建立大应变的本构关系。(4)在折叠过程中进行DTI[和组织学]研究，以表征解剖、微观结构和细胞变化。比较扩散和机械性能的空间、方向和发展变化。意义：这是建立包括生长在内的皮质折叠严格生物力学模型的第一步。需要这样的模型来了解导致精神残疾和疾病（发育迟缓、癫痫发作）的病理（如缺脑症、多小回症）的因果途径。公共卫生相关性：大脑发育过程中皮层折叠紊乱具有严重和持久的后果，但其机制尚不清楚。这个项目是开发一个严格的皮质折叠生物力学模型的第一步，包括生长。需要这样的模型来了解导致精神残疾和疾病（如发育迟缓、癫痫发作）的病理（如无脑畸形、多小回症）的因果途径。

DESCRIPTION (provided by applicant): 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).