In vivo cellular and molecular magnetic resonance imaging of brain functions and injuries

Abstract

As compared with other imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI) provides distinctive advantages with better contrast and resolution in imaging brain anatomy and function in vivo. As compared with electrophysiological and histological tracing techniques, MRI enables longitudinal investigation with higher efficiency, lower labor cost and less possibility of sampling error. The major objective of this doctoral work is to utilize cellular and molecular MRI to investigate normal brain functions and injuries in vivo. The results successfully demonstrated MRI as an efficient and sensitive tool for providing comprehensive assessment of brain injuries for promoting accurate prognosis and timely intervention, and for studying fundamental questions with regard to cortical adaptations to challenges in the young adulthood. Firstly, diffusion tensor imaging (DTI) and T2-weighted imaging were employed to characterize longitudinal neuronal and axonal changes of pyramidal tract (PY), a critical part of corticospinal tract, following experimental intracerebral hemorrhage (ICH). Combining DTI with T2-weighted imaging results, ipsilateral PY injuries following ICH were diagnosed as four stages. Quantitative analysis revealed transient diffusivity decreases in PY both contralateral and ipsilateral to the primary hemorrhagic site. Evolution of the ipsilateral DTI parameters correlated with histological findings and indicated evolving and complex pathological processes underlying monotonic FA decrease. These results demonstrated multi-parametric DTI as a valuable imaging tool for non-invasive and longitudinal monitoring of secondary PY injuries. Secondly, DTI and manganese-enhanced MRI (MEMRI) were utilized to detect neuronal changes of substantia nigra (SN) following experimental ICH in rodents. DTI revealed early changes in SN both contralateral and ipsilateral to the primary hemorrhagic site. Evolution of the ipsilateral parameters correlated with the histological results. MEMRI provided insights into the cellular phenotype changes at the late stage. DTI can serve as a valuable imaging tool for non-invasive early detection and longitudinal monitoring of secondary SN injuries, while MEMRI could complementally provide information regarding the late stage inflammation process. Multi-parametric MRI could facilitate clinical and preclinical investigations of SN injuries for exploring disease mechanisms and developing new therapeutic strategies. Thirdly, MEMRI was performed to characterize the interhemispheric interactions in normal and monocularly deprived rodent visual brain. Characteristic transcallosal manganese labeling was observed in the normal group in a manner consistent with previous histological findings. Significant decrease of such labeling was observed in rats with left or right eyelid suturing, or with left eye enucleation, but not in rats with right eye enucleation. These results demonstrated MEMRI as an efficient tool for investigating interhemispheric interactions both anatomically and functionally. These results also indicated that the adult brain recruits different mechanisms for its adaptations to eyelid suturing and enucleation, thus shedding light on our understanding of the transcallosal interhemispheric excitation and inhibition. Lastly, new paradigms other than pressure injection for intracortical manganese administration in MEMRI were introduced to minimize the neuro-toxicity of manganese and maximize the sensitivity of MEMRI for studying cortical functional changes. Transmeningeal diffusion, osmotic pump-based infusion, and intranasal instillation were demonstrated to be successful in tracing interhemispheric connections and detecting stress-related cortical and subcortical changes.