Disruption of neuronal migration to the cortex is responsible for a host of developmental disorders including severe cognitive impairment, epilepsy, motor and sensory abnormalities, and mild learning disabilities, which are often associated with morphometric abnormalities of the brain including polymicrogyria (PMG) and lissencephaly (US). PMG results from abnormal late cortical organization and is inconstantly associated with abnormal neuronal migration. PMG is a common cortical malformation and is associated with a wide number of patterns and syndromes and with mutations in several genes. In contrast, LIS is characterized by absent or decreased convolutions, producing cortical thickening and a smooth cerebral surface. Recently, even more subtle developmental disturbances of gyral folding have been reported to lead to developmental neurological disorders, suggesting altered brain connectivity. It is therefore essential to develop a clear picture of the patterns and timing of development of brain pathways, and to interpret the role of white matter pathways in order to more accurately diagnose brain dysfunctions during development. In order to accurately diagnose focal and global pathology of neuronal migration disorders, it is crucial to directly image fiber pathways in the whole brain. However, using non-invasive MRI techniques, detection of structural connections through the gray matter/white matter border in the human cerebral cortex remains elusive due to the existence of abundant fiber crossings in the white/gray matter border. Overcoming this problem, high-angular resolution diffusion MR imaging (HARD I) (including O-ball imaging [OBI] and diffusion spectrum imaging [DSI]) is useful to resolve fiber crossings. We have recently further optimized this technique to resolve detailed coherent and crossing structures in the brain even in tissues with low fractional anisotropy which is useful to detect pathways through pathologic regions with migration disorders. Combining the results from this study to an ongoing research program on typically developing brains (Takahashi, R01 HD078561), we will be able to assess in a 3-dimensional manner the pathology of brain pathways in PMG and LIS, which we believe will give us an important insight into the relationships between fiber pathways and gyral structures during development.
We will have broad opportunities to apply this technique to patient populations including neurological and psychiatric disorders. Information regarding the degree to which in vivo results can reproduce ex vivo results in which regions will be important for clinical interpretation of this technique.
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