Magnetic resonance imaging investigation of normal and altered brain functions and metabolisms

Abstract

Benefiting from higher SNR as well as better spatial, temporal and spectral resolution, magnetic resonance imaging (MRI) at high field has proved to be a valuable neuroimaging modality which provides comprehensive evaluation of the central nervous system non-invasively. The objectives of this doctoral work were to develop MRI methodologies and to assess the functional, metabolic and structural alterations in rodent brains under normal and manipulated conditions.

Firstly, to improve the functional sensitivity and spatial precision, a novel functional MRI (fMRI) method using balanced steady state free precession with intravascular susceptibility contrast agent was proposed and its feasibility was evaluated in rat visual system. This new approach was sensitized to cerebral blood volume (CBV) changes. It provided comparable sensitivity to conventional CBVweighted fMRI using echo planar imaging but with no severe image distortion and signal dropout. Robust negative responses during visual stimulation were observed and activation patterns were in excellent agreement with known neuroanatomy. As a promising alternative to conventional CBV-weighted fMRI, it was particularly suited for fMRI investigation of animal models at high field.

Secondly, the relationship between anatomical connections and resting-state fMRI connectivity was explored using a well-controlled animal model of corpus callosotomy. Both complete and partial callosotomy resulted in significant loss of interhemispheric connectivity in the cortical areas whose primary interhemispheric connections via corpus callosum (CC) were severed. Partial restoration of interhemispheric connectivity and increased intrahemispheric connectivity were also observed. The experimental findings directly supported that anatomical connections via CC play a primary and indispensable role in resting-state connectivity, and that resting-state networks could be dynamically reorganized or acquired directly or indirectly through the remaining anatomical connections.

Thirdly, proton magnetic resonance spectroscopy (1H MRS) was employed to monitor the longitudinal metabolic alterations elicited by exogenous stimulation and endogenous modification, respectively. Significantly lower hippocampal N-acetylaspartate (NAA) was observed in fear conditioning animals, indicating reduced neuronal dysfunction and/or integrity, which contributed to the trauma-related symptoms. Meanwhile, pregnant animals exhibited prominently higher hippocampal NAA level, reflecting the increased density of neurons in this region, which might facilitate supporting behaviors that involving learning and memory. The 1H MRS detection of ongoing neurochemical changes induced by fear conditioning and pregnancy, especially in the hippocampus, can shed light on the mechanisms of learning and memory and the neurochemical underpinnings of behavioral improvement in pregnant animals.

Lastly, manganese-enhanced MRI (MEMRI) was employed to investigate the hypoxic-ischemic (HI) injury in the late phase and the neural response to conditioned fear. Significantly higher enhancement in T1-weighted images was found in the peri-lesional region 24 hours after manganese administration and it colocalized with the increase in glial cell density in histological staining, demonstrating the existence of reactive gliosis in the late phase after HI injury. In fear conditioned animals, higher manganese uptake was observed in amygdala, hippocampus, paraventricular nucleus of hypothalamus and cingulate cortex, which were all highly-involved in the process of fear. These findings suggested MEMRI approach were useful in investigation of post-injury cellular events and functional reorganization as well as for in vivo mapping of neuronal activity.