A cardinal sign of Spinocerebellar ataxia (SCA) is dysmetria, defined as endpoint errors in intended movement. A potential consequence, that has largely been unexplored, is that dysmetria contributes to functional motor deficits in SCA. Further, the neurophysiological basis of dysmetria remains poorly understood. More importantly, therapeutic interventions to reduce dysmetria in SCA are underdeveloped. Our preliminary data demonstrate that individuals with SCA6 respond to acute motor practice and are able to reduce leg dysmetria. Further, we found that leg dysmetria strongly correlates to the clinical assessment of function (International Cooperative Ataxia Rating Scale score; ICARS) and to increased motor neuron pool variability in SCA6. Finally, we found that SCA6 individuals have decreased activation of the cerebellar-thalamo-cortical circuit using functional magnetic resonance imaging (fMRI). Based on our preliminary data, we test the central hypothesis that an error-reducing intervention will decrease dysmetria in SCA by increasing the activation of the thalamus and motor cortex and reducing the variability of the motor neuron pool. To address this hypothesis we propose the following two specific aims.
In Aim 1, we will determine if an error-reducing intervention can decrease dysmetria and improve motor function in SCA. To accomplish this Aim, we will recruit 30 SCA (SCA1, SCA3, SCA6) that will be assigned to an error-reduction training group (N=15) or to a best medical management (BMM) control group (N=15). We will quantify dysmetria with errors during goal- directed movements of the ankle and motor function with clinical assessments (ICARS). The error-reduction intervention will be a home-based program using a novel, custom designed computer interface. Participants will train to reduce error during goal-directed movements of the leg to targets in a 3D virtual environment. The intervention will be 4 weeks long for 4 days a week lasting 1 hour on each day. We hypothesize that the error- reducing intervention will lead to reduction in dysmetria and consequently improvements in motor function.
In Aim 2, we will determine the neurophysiological changes that mediate reductions in dysmetria and improve motor function in SCA following an error-reducing intervention. To accomplish this Aim, we will quantify functional changes of the brain with fMRI and changes in motor neuron pool variability by examining the discharge rate variability of multiple motor units. We hypothesize that the error-reducing intervention will increase the functional activity of the thalamus and motor cortex and reduce motor neuron pool variability. This innovative proposal will use novel, cost effective and state-of the-art technology based intervention to address dysmetria and significantly impact the current rehabilitation of SCA.
A cardinal sign of Spinocerebellar ataxia (SCA) is dysmetria, which contributes to functional motor deficits in SCA. Despite this, motor interventions to reduce dysmetria in SCA are underdeveloped. The purpose of this grant is to develop a home-based motor intervention to reduce dysmetria and improve motor function in SCA, and determine the neurophysiological mechanisms that mediate these improvements. The proposed studies will implement a novel, engaging, and cost-effective intervention to impact SCA rehabilitation.
| Kang, Nyeonju; Christou, Evangelos A; Burciu, Roxana G et al. (2017) Sensory and motor cortex function contributes to symptom severity in spinocerebellar ataxia type 6. Brain Struct Funct 222:1039-1052 |
