Developmental sensorimotor and cognitive pathways in infant cerebellum with multi-scale imaging

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PROJECT SUMMARY Development of the human cerebellum undergoes a precisely programmed sequence of processes, spanning from the third trimester of pregnancy into the first postnatal year. Due to advances in neonatal imaging techniques, cerebellar injury has been increasingly detected in premature infants and full-terms with birth complications. Although perinatal cerebellar injury and malformation have been broadly associated with developmental delays in motor, language, cognition, and social behaviors, the underlying biological processes – causing the functional disorders – have not yet been fully understood. Existing studies have reported conflicting findings regarding the role regional cerebellum lesions play in motor and socio-cognitive disorders, which are especially challenging in secondary cerebellar malformation where contralateral cerebral injury is a substantial confounder. Our exploratory study proposes to address these controversial findings by developing a multi-scale imaging framework to elucidate the neuroarchitecture and connectivity maps of the first-year cerebellum development. The framework builds on our preliminary work of 100-500µm-resolution ex vivo magnetic resonance imaging (MRI) and diffusion MRI as well as 3-10µm-resolution automated serial-sectioning polarization sensitive optical coherence tomography (as-PSOCT). Essentially, as-PSOCT uses intrinsic optical properties and adopts a block-face strategy to eliminate tissue distortion in conventional histology and reveal cellular organizations, myelin content, and orientation of fiber tracts with microscopic precision in volumetric reconstruction. By co-registering it with the ex vivo MRI on the same sample, cellular level information will be transferred to the coordinates of the entire brain space. The study design will optimize scan protocols to uncover sophisticated folding patterns as well as small and less myelinated fiber tracts in the developing cerebellum. Computational models will be developed to aid cross-modality registration, multi-resolution image fusion and white matter tractography. The successful completion of this project will, for the first time, generate high- resolution maps to characterize cerebellar structure and connectivity within the first year of life. The project will advance our understanding of the role human cerebellum plays in higher cognitive functions. The cerebellar atlas and connectivity map offer a reference for future clinical evaluations in neurodevelopmental delays in the human cerebellum. Additionally, the multi-scale technique serves as a more general, intriguing tool for the neuroscience community to conduct cellular-to-system level investigations in the brain.