This grant application details a plan for mentored research and didactic training in an enriched academic environment that will provide the candidate with the knowledge and skills to conduct independent research that has important implications for both basic visual neuroscience and clinical neuro-ophthalmology. The candidate is a neurologist with some prior exposure to eye movement and vestibular disorders and structural neuroimaging techniques. This award will enable the candidate to expand her research skills to develop better models of basic ocular motor control mechanisms in cerebellar disease and to implement these models into a clinically useful schema for understanding the mechanisms of the disabling diplopia and oscillopsia often suffered by patients with cerebellar disease. The candidate will acquire new skills in two complementary areas: 1) developing physiological and mathematical models of ocular motor learning, and 2) acquisition and analysis of structural and functional MRI, including their application to control systems modeling. The didactic and research components will be conducted under the mentorship of Dr. David Zee, who has expertise in clinical, ocular motor, and control-systems characterization of cerebellar ataxia syndromes as well as experience in structural and functional MR imaging of the ocular motor system. Dr. Jerry Prince, who has expertise in image processing and brain mapping algorithms, and Dr. Michael Kraut, who has expertise in neurophysiology and functional neuroimaging of visual and somatomotor function, will serve as primary collaborators and will supervise neuroimaging aspects of the training plan, including refinement of high resolution MR techniques for structural and functional imaging. Dr. Neil Miller at the Wilmer Eye Institute will help train Dr. Ying in clinical neuro-ophthalmology and will also emphasize the clinical implications of her research. The research component will involve development of a deformable multidimensional probabilistic brain atlas that will incorporate features of genotype, clinical presentation, functional measures of eye movements, and morphometry for two model populations, SCA2 and SCA6, which are genetically-defined cerebellar ataxia syndromes with complementary ocular motor phenotypes. This anatomically based schema will enable us to elucidate models of basic eye movement control and ocular motor learning, with an emphasis on gaze holding and on phoria adaptation. We will test the hypothesis that abnormalities of brain structure and function are genotype-specific and are associated with progression of disease. Understanding these structure-function relationships in the control of eye movements has important implications for every aspect of cerebellar disease, from diagnosis to clinical management to development of rehabilitative strategies, and may be applicable to other degenerative disease in which there are visual disturbances associated with ocular misalignment and abnormal eye movements.
