Pathophysiology of Upper and Lower Limb Motor Control in Spinocerebellar Ataxia

University Of Florida, Gainesville FL

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Abstract

? DESCRIPTION (provided by applicant): The cerebellum is crucial in upper and lower limb motor control, and people with cerebellar damage can have difficulty with upper and lower limb motor functions. One form of cerebellar damage is that in spino- cerebellar ataxia (SCA) 6. It is caused by mutations in the CACNA1A gene and causes relatively pure cerebellar degeneration. The majority of the neuroimaging work in SCA-6 has used structural magnetic resonance imaging (MRI), and these studies point to degeneration isolated to the brain stem and cerebellum. Despite advances in genetic and structural MRI characterizations of SCA-6, we still do not understand how the functional brain networks between the cerebellum and cortex are affected in SCA-6. We also have yet to link specific functional changes in the brain and muscle with clinically-relevant upper and lower limb motor functions. Although structurally the thalamus and cortex may seem intact in SCA-6 patients, this does not imply that the thalamus and cortex are functioning normally in SCA-6. If the cortex and thalamus are also affected in SCA-6, this would open the door for potential therapies that either stimulate or target specific receptors in the thalamus and cortex. One advantage of task-based functional magnetic resonance imaging (fMRI) and functional connectivity is these methods will respond to acute treatments, and can provide a research and drug development platform to test new therapies for ataxia in SCA-6. The long-term goal of this work is to develop a motor physiology platform to evaluate target engagement and test novel therapies in SCA-6 and other SCAs. The first step is to understand the basic pathophysiology of SCA-6 which will be achieved in this R21. We propose to characterize: 1) the state of cerebellar, thalamic, and cortical functional activity using task-basd fMRI, 2) the functional connectivity between the cerebellum and cortex while probing circuits specific to upper and lower limbs, and 3) the activation of the motor unit pool of a hand muscle used in gripping objects and the ankle dorsiflexors which are used in lower limb motor control. We will then determine if the pathophysiology assayed across of brain and muscle relates to upper and lower limb motor functions using the International Cooperative Ataxia Rating Scale (ICARS). The outcome of this work will help us achieve our long-term goal of developing a motor physiology platform to evaluate target engagement and testing novel therapies in SCA-6 and other forms of ataxia.