Although the symptomology of multiple sclerosis (MS) has been described for decades, an understanding of the mechanisms and causes of the disease are only now emerging. Early signatures of multiple sclerosis (MS) often involve degradation of visual acuity, sometimes resulting in episodes of double vision and even blindness. Visual evoked potentials (VEPs) are widely used to asses patients suspected have having MS because of their high sensitivity for detecting even clinically silent lesions of the visual pathway. Although increased VEP latency and broadened waveforms are taken to indicate lesions, little is known of the exact relationship (s) between the VEP and the sizes, locations or histories of lesions. Investigating such relationships would require some means to perform longitudinal histopathological studies of the optic nerve. The proposed experiments will draw upon recent advances in magnetic resonance imaging microscopy (uMRI) to perform longitudinal in vivo imaging studies of the optic nerve in mice. These uMRI methods are based on qualitative measurements of local water diffusion. Pilot experiments, in which the techniques have been applied to fixed spinal cords from nice demonstrate that the approach offers unprecedented sensitivity tot the trajectories and myelination of nerve tracks. The goal here is to harness the potential of these new uMRI methods to perform longitudinal, in vivo studies of the demyelination of the optic nerve and correlate these with the VEPs, performed on the same animals, as a functional assay for visual function. The studies will employ a strain of transgenic mice which experience spontaneous demyelination of the central nervous system (CNS), with episodic weakness and demyelination similar to MS, making it an appropriate model system for the technical developments and experiments proposed here. Quantitative MRI measurements of water diffusion will be performed hind-in-hind with theoretical modeling of the diffusion though neural tissues to develop a sensitive and high-resolution probe of myelination in vivo. By performing quantitative uMRI measurements on the same animal, and correlating these images with longitudinal measurements of the VEP and with conventional histopathalogical analyses of the same animal, the goal is to permits a one-to-one comparison between the anatomy, physiology and symptomology of a demyelinating disease, modeling and the longitudinal imaging studies described in this proposal.
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