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.

Public Health Relevance

SCAs are debilitating disorders that result in ataxia and other problems with movement. Most SCAs have a known genetic underpinning, yet we know very little about the brain pathways involved in various SCAs, and how each brain pathway functions. We will test neuroimaging and neuromuscular physiology of SCA-6 and control individuals to ascertain the specific circuits and pathways that relate to deficits in upper and lower limb function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS093695-01
Application #
8953096
Study Section
Musculoskeletal Rehabilitation Sciences Study Section (MRS)
Program Officer
Gwinn, Katrina
Project Start
2015-07-01
Project End
2017-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Florida
Department
Physiology
Type
Sch Allied Health Professions
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611